Substituted tetrahydrobenzothienopyrimidinamine compounds useful for treating hyper-proliferative disorders

ABSTRACT

The present invention relates to a compound of Formula (I) and its use in treating lung and breast cancer.

This application claims benefit of U.S. Provisional Application Ser. No.60/490,335, filed Jul. 24, 2003, the contents of which are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to novel substitutedtetrahydrobenzothienopyrimidinamine compounds, pharmaceuticalcompositions containing such compounds and the use of those compoundsand compositions for the treatment of hyper-proliferative disorders.

DESCRIPTION OF THE INVENTION

One embodiment of the present invention relates to a compound of FormulaI

wherein

-   R is in each instance selected independently from H, (C₂–C₆)alkenyl,    C(O)R⁶, hydroxy, NR⁸⁻¹R⁸⁻¹, and

-    or-   R is (C₁–C₆)alkyl said alkyl being optionally mono-substituted with    R⁷,

with the proviso that when one R is H, the other R must be other than Hor methyl, and with the further proviso that when one R is hydroxy, theother R must be other than hydroxy;

-   R¹ is selected from H, OH, halo, CN, NH₂, CF₃, OCF₃, (C₁–C₃)alkyl,    (C₂–C₃)alkynyl, and    -   (C₁–C₃)alkoxy;-   R² is selected from H, OH, halo, NH₂, CN, CF₃, OCF₃, (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   (C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionally        substituted with 1, 2 or 3 substituents each selected        independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN,        and OH,    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;    -   O-pyridyl optionally substituted with 1, 2 or 3 substituents        each selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy,        halo, CF₃, CN, and OH;-   R³ is selected from H, OH, halo, NH₂, CN, CF₃, OCF₃, (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH,    -   (C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionally        substituted with 1, 2 or 3 substituents each selected        independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN,        and OH,    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH,    -   O-pyridyl optionally substituted with 1, 2 or 3 substituents        each selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy,        halo, CF₃, CN, and OH; or-   R² and R³ together with the carbon atoms to which they are attached    form a pyrazole, where said pyrazole is optionally substituted with    1 or 2 substituents each selected independently from methyl, ethyl    and benzyl or pyridylmethyl, wherein benzyl and pyridylmethyl can    optionally be substituted with 1 or 2 substituents each selected    independently from methyl, halo, cyano and methoxy;-   R⁴ is selected from H, OH, halo, CN, CF₃, OCF₃, NH₂ (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy, trifluoromethyl, trifluoromethoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   (C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionally        substituted with 1, 2 or 3 substituents each selected        independently from (C₁–C₃)alkyl,    -   (C₁–C₃)alkoxy, halo, CF₃, CN, and OH,    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;    -   O-pyridyl optionally substituted with 1, 2 or 3 substituents        each selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy,        halo, CF₃, CN, and OH; or-   R⁵ is selected from H, OH, halo, CN, CF₃, OCF₃, NH₂, (C₁–C₃)alkyl,    (C₂–C₃)alkynyl, and (C₁–C₃)alkoxy;-   R⁶ is selected from OH, (C₁–C₆)alkyl, (C₁–C₃)alkoxy, phenyl,    pyridyl, NR⁸R⁸,

-   -   NH(C₂–C₆)alkenyl, and    -   a five membered heterocycle optionally substituted with a        substituent selected from OH, N[(C₁–C₃)alkyl]₂, and        (C₁–C₃)alkyl, said alkyl being optionally substituted with a        substituent selected from OH, (C₁–C₃)alkoxy, and

-   R⁷ is selected from OH, halo, (C₁–C₄)alkoxy, phenoxy optionally    substituted with halo or amino, C(O)R⁶, halo, NR⁸R⁸, imidazolyl,    phenyl, indazolyl, aminoindazolyl, —OS(O)₂C₁–C₃),

-   -   NHC(O)NR⁸R⁸, NHS(O)₂R⁹, NHC(O)-pyrrolidinyl,    -   NHC(O)-morpholinyl, and    -   pyrrolidinyl optionally substituted with one or two substituents        selected from hydroxy, (C₁–C₃)alkoxy, N[(C₁–C₃)alkyl]₂, and        (C₁–C₃)alkyl optionally mono-substituted with hydroxy or        (C₁–C₃)alkoxy;

-   R⁸ is in each instance selected independently from H, pyridyl,    -   (C₁–C₄)alkyl optionally mono-substituted with hydroxy,        (C₁–C₃)alkoxy, —S(O)₂(C₁–C₃)alkyl, NR¹⁰R¹⁰, or

-   -    and    -   phenyl optionally substituted with 1, 2, or 3 substituents each        independently selected from CN, OH, halo, CF₃, NR¹⁰R¹⁰ and        (C₁–C₃)alkoxy, or

-   -   wherein n is a number from 1 to 5 and R¹⁰ is selected from H and        (C₁–C₃)alkyl;

-   R⁸⁻¹ is in each instance selected independently from H, and    -   (C₁–C₄)alkyl optionally mono-substituted with (C₁–C₃)alkoxy,        NR¹⁰R¹⁰, or

-   R⁹ is selected from (C₁–C₃)alkyl, pyridyl, thienyl, and phenyl where    said phenyl is optionally substituted with 1, 2, or 3 substituents    each independently selected from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, CN,    OH, halo, CF₃, and NR⁸R⁸;-   R¹⁰ is selected from H and (C₁–C₃)alkyl;-   Z is selected from CH₂, O, S, SO, SO₂, and NH, and    -   when Z is NH, H is optionally replaced with pyridyl,        -   (C₁–C₃)alkyl optionally substituted with a substituent            selected from hydroxy, (C₁–C₃)alkoxy and pyridyl, or        -   phenyl optionally substituted with 1, 2, or 3 substituents            each independently selected from (C₁–C₃)alkyl,            (C₁–C₃)alkoxy, CN, halo, CF₃, and NR⁸R⁸;-   Z¹ is selected from CH₂, O, S, SO, SO₂, and NH, and    -   when Z¹ is NH, H is optionally replaced with pyridyl,        -   (C₁–C₃)alkyl optionally substituted with a substituent            selected from hydroxy, (C₁–C₃)alkoxy and pyridyl, or        -   phenyl optionally substituted with 1, 2, or 3 substituents            each independently selected from (C₁–C₃)alkyl,            (C₁–C₃)alkoxy, CN, halo, CF₃, and NR⁸R⁸;            or a pharmaceutically acceptable salt or ester thereof,            excluding the following compounds:-   5,6,7,8-tetrahydro-7-methyl-N-[4-(phenylmethoxy)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-amine,    monohydrochloride;-   5,6,7,8-tetrahydro-N-(4-methoxyphenyl)-7-methyl-[1]benzothieno[2,3-d]pyrimidin-4-amine,    monohydrochloride;-   5,6,7,8-tetrahydro-7-methyl-N-[3-(trifluoromethyl)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine;-   N-(3,4-dimethylphenyl)-5,6,7,8-tetrahydro-7-methyl    [1]benzothieno-[2,3-d]pyrimidin-4-amine.

The terms have the following meaning throughout:

The term “optionally substituted” means that the moiety so modified mayhave from none to up to at least the highest number of substituentsindicated. The substituent may replace any H atom on the moiety somodified as long as the replacement is chemically possible andchemically stable. When there are two or more substituents on anymoiety, each substituent is chosen independently of any othersubstituent and can, accordingly, be the same or different.

-   The terms “(C₁–C₃)alkyl” and “(C₁–C₆)alkyl” mean a linear or    branched saturated hydrocarbon radical having from about 1 to about    3 or about 6 C atoms, respectively. Such groups include but are not    limited to methyl, ethyl, n-propyl, isopropyl, and the like.-   The term “(C₁–C₃)alkoxy” means a linear or branched saturated    hydrocarbon radical having from about 1 to about 3 C atoms, said    radical being attached to an O atom. The O atom is the point of    attachment of the alkoxy substituent to the rest of the molecule.    Such groups include but are not limited to methoxy, ethoxy,    n-propoxy, isopropoxy, and the like.-   The term “(C₁–C₃)alkoxy-phenyl” means a phenyl group bonded to the    alkyl portion of an alkoxy group, as alkoxy is defined above. The    phenyl group is bonded to any accessible primary or secondary C atom    in the alkyl portion of the alkoxy-phenyl group, and the    alkoxy-phenyl group is attached to the rest of the molecule through    the O atom.

The term “(C₁–C₃)alkoxy-pyridyl” means a pyridyl group bonded to thealkyl portion of an alkoxy group, as alkoxy is defined above. Thepyridyl group is bonded to any accessible primary or secondary C atom inthe alkyl portion of the alkoxy-pyridyl group, and the alkoxy-pyridylgroup is attached to the rest of the molecule through the O atom.

The term “O-phenyl” means a phenyl group bonded to an O atom. The O atomis the point of attachment of the group to the rest of the molecule.

The term “(C₂–C₆)alkenyl” means a linear or branched carbon group havingfrom about 2 to about 6 C atoms wherein at least two adjacent C atoms inthe alkenyl group are joined by a double bond, with the proviso thatwhen a C atom is double bonded to one adjacent C atom, it must be singlebonded to any other adjacent C atom. The alkenyl group is attached tothe rest of the molecule through a single bond.

The term “(C₂–C₆)alkynyl” means a linear or branched carbon group havingfrom about 2 to about 6 C atoms wherein there is at least one triplebond between two adjacent C atoms in the group with the proviso thatwhen a C atom is triple bonded to one adjacent C atom, it must be singlebonded to any other adjacent C atom. The alkynyl group is attached tothe rest of the molecule through a single bond.

The term “halo” means Cl, Br, F or I.

When “(O)” is used in a chemical formula, it means an O atom that isdouble bonded to the atom to which it is attached, but is not furtherbonded to any other atom, for example, “C(O)” represents a carbonylgroup.

The formulae “N[C₁–C₃)alkyl]₂”, “NR⁸R⁸”, “NR⁸⁻¹R⁸⁻¹” and “NR¹⁰R¹⁰” eachmeans that each of the 2 possible groups attached to the N atom areselected independently from the other so that they may be the same orthey may be different.

The term “a five membered heterocycle” means a ring made of 5 atoms, 1,2 or 3 of which are N with the remaining atoms being C. The heterocycleis saturated, unsaturated or partially saturated. Five memberedheterocycles include but are not limited to pyrrolyl, imidazolyl,pyrazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, pyrazolinyl, triazolyl, and the like. The heterocycle isattached to the rest of the molecule through a bond attached to theheterocycle at any position of the heterocyclic radical from which a Hatom could conceptually have been removed to create the radical from itscorresponding stand-alone molecule.

When a phenyl ring, pyridyl ring, or a five membered heterocycle isattached to the rest of the molecule, the bond to the rest of themolecule is attached to the radical at any position of the radical fromwhich a H could conceptually have been removed to create the radicalfrom its corresponding stand-alone molecule.

When prefixes such as (C₁–C₄) are used before substituents, they mean toindicate the respective number of carbon atoms, in this case 1 to 4.

A * symbol next to a bond denotes the point of attachment in themolecule.

Except for intermediates, chemically unstable compounds are lesspreferred in the context of the present invention. Chemically unstablehere is meant to include conditions to which a compound is exposed whenadministered to a patient in need thereof, such as acidic or basicconditions of the gastrointestinal tract. For example, a chemicallyunstable compound would be one where two nitrogen or oxygen substituentsare bonded to a single aliphatic carbon atom. Another example of achemically unstable compound would be one where an alkoxy group isbonded to the unsaturated carbon of an alkene to form an enol ether.Furthermore, an aliphatic carbon atom attached to oxygen may not alsobear a chloro, bromo or iodo substituent, and when any alkyl group isattached to O, S, or N, and bears a hydroxyl substituent, then thehydroxyl substituent is separated by at least two carbon atoms from theO, S, or N to which the alkyl group is attached.

Another embodiment of the present invention relates to a compound ofFormula (I), wherein

-   R is selected independently from hydrogen and C(O)R⁶, or-   R is (C₁–C₆)alkyl said alkyl being optionally mono-substituted with    R⁷;-   with the proviso that when one R is H, the other R must be other    than H or methyl;-   R¹ is selected from H, OH, halo, CN, NH₂, CF₃, methyl, ethyl,    ethynyl, methoxy, and ethoxy;-   R² is selected from H, OH, halo, NH₂, CN, CF₃, (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   (C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionally        substituted with 1, 2 or 3 substituents each selected        independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN,        and OH,    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;-   R³ is selected from H, OH, halo, NH₂, CN, CF₃, (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH,    -   (C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionally        substituted with 1, 2 or 3 substituents each selected        independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN,        and OH,    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH,    -   O-pyridyl optionally substituted with 1, 2 or 3 substituents        each selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy,        halo, CF₃, CN, and OH; or-   R² and R³ together with the carbon atoms to which they are attached    form a pyrazole, where said pyrazole is optionally N-substituted    with 1 substituent selected from methyl, ethyl and benzyl;-   R⁴ is H;-   R⁵ is H;-   R⁶ is selected from NR⁸R⁸,

-   -   NH(C₂–C₆)alkenyl and    -   a five membered heterocycle optionally substituted with a        substituent selected from OH, N[(C₁–C₃)alkyl]₂, and        (C₁–C₃)alkyl, said alkyl being optionally substituted with a        substituent selected from OH, (C₁–C₃)alkoxy, and

-   R⁷ is selected from phenoxy optionally substituted with halo or    amino, NR⁸R⁸, imidazolyl, indazolyl, aminoindazolyl,

-   -   NHC(O)NR⁸R⁸, NHS(O)₂R⁹, NHC(O)-pyrrolidinyl,    -   NHC(O)-morpholinyl, and    -   pyrrolidinyl optionally substituted with one substituent        selected from (C₁–C₃)alkoxy,    -   N[(C₁–C₃)alkyl]₂, and (C₁–C₃)alkyl optionally mono-substituted        with (C₁–C₃)alkoxy;

-   R⁸ is in each instance selected independently from H, pyridyl,    -   (C₁–C₄)alkyl optionally mono-substituted with (C₁–C₃)alkoxy,        —S(O)₂(C₁–C₃)alkyl, NR¹⁰R¹⁰, or

-   -    and    -   phenyl optionally substituted with 1, 2, or 3 substituents each        independently selected from CN, OH, halo, CF₃, NR¹⁰R¹⁰ and        (C₁–C₃)alkoxy;

-   R⁹ is selected from (C₁–C₃)alkyl, pyridyl, thienyl, and phenyl where    said phenyl is optionally substituted with 1, 2, or 3 substituents    each independently selected from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, CN,    OH, halo, CF₃, and NR⁸R⁸;

-   R¹⁰ is selected from H and (C₁–C₃)alkyl;

-   Z is selected from CH₂, O, S and NH, and    -   when Z is NH, H is optionally replaced with pyridyl,        -   (C₁–C₃)alkyl optionally substituted with a substituent            selected from hydroxy, (C₁–C₃)alkoxy and pyridyl, or        -   phenyl optionally substituted with 1, 2, or 3 substituents            each independently selected from (C₁–C₃)alkyl,            (C₁–C₃)alkoxy, CN, halo, CF₃, and NR⁸R⁸;            or a pharmaceutically acceptable salt or ester thereof,            excluding the following compounds:

-   5,6,7,8-tetrahydro-7-methyl-N-[4-(phenylmethoxy)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine,    monohydrochloride;

-   5,6,7,8-tetrahydro-N-(4-methoxyphenyl)-7-methyl-[1]benzothieno[2,3-d]pyrimidin-4-amine,    monohydrochloride;

-   5,6,7,8-tetrahydro-7-methyl-N-[3-(trifluoromethyl)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine;

-   N-(3,4-dimethylphenyl)-5,6,7,8-tetrahydro-7-methyl    [1]benzothieno-[2,3-d]pyrimidin-4-amine.

Another embodiment of the present invention relates to a compound ofFormula I, wherein

-   one R is hydrogen and the other R is methyl, ethyl or propyl, said    methyl, ethyl or propyl being mono-substituted with R⁷; and-   R⁷ is selected from hydroxy, NR⁸R⁸,

-    NHC(O)NR⁸R⁸, NHS(O)₂R⁹, NHC(O)-pyrrolidinyl, and    NHC(O)-morpholinyl.

Another embodiment of the present invention relates to a compound ofFormula I of claim 1, wherein R³ is 4-fluorobenzyloxy,3-fluorobenzyloxy.

Another embodiment of the present invention relates to a compound ofFormula I of claim 1, wherein R³ is a dihalogenated phenyl, e.g. whereinhalo is fluoro or chloro, such as 3-chloro-4-fluorophenyl.

Another embodiment of the present invention relates to a compound ofFormula I of claim 1, wherein R³ is meta-substituted phenyl, such as3-bromophenyl or 3-ethynylphenyl.

Another embodiment of the present invention relates to a compound ofFormula I, wherein

-   R is in each instance selected independently from H, (C₂–C₆)alkenyl,    C(O)R⁶ and    -   (C₁–C₆)alkyl said alkyl being optionally mono-substituted with        R⁷,    -   with the proviso that when one R is H, the other R must be other        than H;-   R¹ is selected from H, OH, halo, CN, NH₂, CF₃, (C₁–C₃)alkyl, and    -   (C₁–C₃)alkoxy;-   R² is selected from H, OH, halo, NH₂, CN, CF₃, (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;-   R³ is selected from H, OH, halo, NH₂, CN, CF₃, (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;-   R⁴ is selected from H, OH, halo, CN, CF₃, NH₂ (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;-   R⁵ is selected from H, OH, halo, CN, CF₃, NH₂, (C₁–C₃)alkyl, and    (C₁–C₃)alkoxy;-   R⁶ is selected from OH, (C₁–C₆)alkyl, (C₁–C₃)alkoxy, phenyl,    pyridyl, NR⁸R⁸,

-    NH(C₂–C₆)alkenyl, and    -   a five membered heterocycle optionally substituted with a        substituent selected from OH, N[(C₁–C₃)alkyl]₂, and        -   (C₁–C₃)alkyl, said alkyl being optionally substituted with a            substituent selected from OH, (C₁–C₃)alkoxy, and

-   R⁷ is selected from OH, (C₁–C₄)alkoxy, C(O)R⁶, halo, NR⁸R⁸,    imidazolyl, phenyl,

-   -   NHC(O)NR⁸R⁸, NHS(O)₂R⁹, NHC(O)-pyrrolidinyl,    -   NHC(O)-morpholinyl, and    -   pyrrolidinyl optionally substituted with one substituent        selected from (C₁–C₃)alkoxy,        -   N[(C₁–C₃)alkyl]₂, and (C₁–C₃)alkyl optionally            mono-substituted with (C₁–C₃)alkoxy;

-   R⁸ is in each instance selected independently from H, pyridyl,    -   (C₁–C₄)alkyl optionally mono-substituted with (C₁–C₃)alkoxy,        S(O)₂(C₁–C₃)alkyl, NR¹⁰R¹⁰, or

-   -    and    -   phenyl optionally substituted with 1, 2, or 3 substituents each        independently selected from CN, OH, halo, CF₃, NR¹⁰R¹⁰ and        (C₁–C₃)alkoxy;

-   R⁹ is selected from (C₁–C₃)alkyl, pyridyl, thienyl, and phenyl where    said phenyl is optionally substituted with 1, 2, or 3 substituents    each independently selected from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, CN,    OH, halo, CF₃,and NR⁸R⁸;

-   R¹⁰ is selected from H and (C₁–C₃)alkyl;

-   Z is selected from CH₂, O, S and NH, and    -   when Z is NH, H is optionally replaced with pyridyl,        -   (C₁–C₃)alkyl optionally substituted with a substituent            selected from (C₁–C₃)alkoxy and pyridyl, or        -   phenyl optionally substituted with 1, 2, or 3 substituents            each independently selected from (C₁–C₃)alkyl,            (C₁–C₃)alkoxy, CN, halo, CF₃, and NR⁸R⁸;            or a pharmaceutically acceptable salt or ester thereof,            excluding the following compounds:

-   5,6,7,8-tetrahydro-7-methyl-N-[4-(phenylmethoxy)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine,    monohydrochloride;

-   5,6,7,8-tetrahydro-N-(4-methoxyphenyl)-7-methyl-[1]benzothieno[2,3-d]pyrimidin-4-amine,    monohydrochloride;

-   5,6,7,8-tetrahydro-7-methyl-N-[3-trifluoromethyl)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine;

-   N-(3,4-dimethylphenyl)-5,6,7,8-tetrahydro-7-methyl    [1]benzothieno-[2,3-d]pyrimidin-4-amine.

In another embodiment, the present invention relates to a method oftreating a hyper-proliferative disorder comprising the administration toa patient in need thereof of an effective amount of a compound ofFormula I.

In another embodiment, the present invention relates to a method oftreating a hyper-proliferative disorder comprising the administration toa patient in need thereof of an effective amount of a compound ofFormula I

wherein

-   R is in each instance selected independently from H, (C₂–C₆)alkenyl,    C(O)R⁶ and    -   (C₁–C₆)alkyl said alkyl being optionally mono-substituted with        R⁷,    -   with the proviso that when one R is H, the other R must be other        than H;-   R¹ is selected from H, OH, halo, CN, NH₂, CF₃, (C₁–C₃)alkyl, and    -   (C₁–C₃)alkoxy;-   R² is selected from H, OH, halo, NH₂, CN, CF₃, (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;-   R³ is selected from H, OH, halo, NH₂, CN, CF₃, (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;-   R⁴ is selected from H, OH, halo, CN, CF₃, NH₂ (C₁–C₃)alkyl,    (C₂–C₆)alkynyl,    -   (C₁–C₃)alkoxy,    -   (C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted        with 1, 2 or 3 substituents each selected independently from        (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, and    -   O-phenyl optionally substituted with 1, 2 or 3 substituents each        selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo,        CF₃, CN, and OH;-   R⁵ is selected from H, OH, halo, CN, CF₃, NH₂, (C₁–C₃)alkyl, and    (C₁–C₃)alkoxy;-   R⁶ is selected from OH, (C₆–C₆)alkyl, (C₁–C₃)alkoxy, phenyl,    pyridyl, NR⁸R⁸,

-    NH(C₂–C₆)alkenyl, and    -   a five membered heterocycle optionally substituted with a        substituent selected from OH, N[(C₁–C₃)alkyl]₂, and        -   (C₁–C₃)alkyl, said alkyl being optionally substituted with a            substituent selected from OH, (C₁–C₃)alkoxy, and

-   R⁷ is selected from OH, (C₁–C₄)alkoxy, C(O)R⁶, halo, NR⁸R⁸,    imidazolyl, phenyl,

-   -   NHC(O)NR⁸R⁸, NHS(O)₂R⁹, NHC(O)-pyrrolidinyl,    -   NHC(O)-morpholinyl, and    -   pyrrolidinyl optionally substituted with one substituent        selected from (C₁–C₃)alkoxy,        -   N[(C₁–C₃)alkyl]₂, and (C₁–C₃)alkyl optionally            mono-substituted with (C₁–C₃)alkoxy;

-   R⁸ is in each instance selected independently from H, pyridyl,    -   (C₁–C₄)alkyl optionally mono-substituted with (C₁–C₃)alkoxy,        S(O)₂(C₁–C₃)alkyl, NR¹⁰R¹⁰, or

-   -    and    -   phenyl optionally substituted with 1, 2, or 3 substituents each        independently selected from CN, OH, halo, CF₃, NR¹⁰R¹⁰ and        (C₁–C₃)alkoxy;

-   R⁹ is selected from (C₁–C₃)alkyl, pyridyl, thienyl, and phenyl where    said phenyl is optionally substituted with 1, 2, or 3 substituents    each independently selected from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, CN,    OH, halo, CF₃, and NR⁸R⁸;

-   R¹⁰ is selected from H and (C₁–C₃)alkyl;

-   Z is selected from CH₂, O, S and NH, and    -   when Z is NH, H is optionally replaced with pyridyl,        -   (C₁–C₃)alkyl optionally substituted with a substituent            selected from (C₁–C₃)alkoxy and pyridyl, or        -   phenyl optionally substituted with 1, 2, or 3 substituents            each independently selected from (C₁–C₃)alkyl,            (C₁–C₃)alkoxy, CN, halo, CF₃, and NR⁸R⁸;            or a pharmaceutically acceptable salt or ester thereof,            excluding the following compounds:

-   5,6,7,8-tetrahydro-7-methyl-N-[4-(phenylmethoxy)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine,    monohydrochloride;

-   5,6,7,8-tetrahydro-N-(4-methoxyphenyl)-7-methyl-[1]benzothieno[2,3-d]pyrimidin-4-amine,    monohydrochloride;

-   5,6,7,8-tetrahydro-7-methyl-N-[3-(trifluoromethyl)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine;

-   N-(3,4-dimethylphenyl)-5,6,7,8-tetrahydro-7-methyl    [1]benzothieno-[2,3-d]pyrimidin-4-amine.

In another embodiment, the present invention relates to a process formaking a compound of formula (I), wherein

-   a compound of formula (II)

-    wherein R has the meaning indicated above,-   is reacted with a compound of formula (III)

-    wherein R¹ to R⁵ have the meaning indicated above, preferably in    the presence of an acid.

Representative compounds of Formula I are described in Table 1 below.

TABLE 1 LCMS RT (min)^(a) or LCMS Ex. TLC R_(f) Ion No. Structure[solvent] [M + H]⁺ 1

2.83 404 2

3.00 424 3

3.12 446 4

2.26 431 5

2.68 447 6

3.39 489 7

2.32 475 8

2.78 449 9

2.80 491 10

2.91 493 11

2.21 435 12

2.16 433 13

2.62 460 14

3.48 432 15

2.58 446 16

2.62 435 17

2.25 421 18

2.69 473 19

2.27 504 20

2.77 378 21

2.14 486 22

2.09 490 23

2.79 479 24

3.41 406 25

2.20 459 26

2.02 472 27

3.15 471 28

3.27 449 29

2.60 461 30

2.29 457 31

2.80 475 32

3.19 460 33

2.30 435 34

2.25 465 35

2.25 477 36

2.23 463 37

2.20 447 38

2.02 502 39

2.56 384 40

2.39 370 41

3.67 498 42

3.45 406 43

2.22 514 44

3.19 386 45

2.30 473 46

2.00 356 47

1.83 342 48

3.16 573 49

2.62 578 50

3.09 470 51

2.81 378 52

2.44 483 53

2.49 358 54

2.22 447 55

2.17 470 56

2.78 444 57

3.49 420 58

2.20 474 59

2.07 460 60

2.15 501 61

2.78 461 62

2.58 449 63

3.39 446 64

2.83 378 65

2.91 420 66

2.02 487 67

3.08 459 68

2.21 502 69

2.20 530 70

2.73 487 71

3.13 485 72

2.76 392 73

2.34 445 74

2.30 431 75

2.28 435 76

2.53 483 77

2.61 523 78

2.12 516 79

2.38 471 80

2.06 486 81

3.04 471 82

2.63 475 83

2.84 491 84

2.26 509 85

2.33 457 86

2.30 461 87

2.31 475 88

2.33 454 89

2.54 509 90

3.33 418 91

2.31 544 92

2.21 516 93

2.11 530 94

2.09 502 95

2.11 432 96

2.30 449 97

2.26 483 98

2.07 448 99

2.13 577 100

2.09 474 101

3.27 392 102

2.91 404 103

2.17 577 104

1.72 512 105

2.33 518 106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

R_(f) = 0.3[30%[EtOAc/Hex] 526.2 137

3.36 484 138

R_(f) = 0.9[50%EtOAc/Hex] 546.3 139

2.64 553 140

2.13 580/582 141

2.07 563/565 142

R_(f) = 0.1[5%MeOH/DCM] 541.2 143

R_(f) = 0.2[30%EtOAc/Hex] 526/528 144

R_(f) = 0.2[80%EtOAc/Hex] 567/569 145

R_(f) = 0.27[5:95MeOH/DCM] 553/555 146

R_(f) = 0.2[5:95MeOH:DCM] 555/557 147

3.20 603/605 148

2.73 594/596 149

R_(f) = 0.23[5:95MeOH/DCM] 551/553 150

R_(f) = 0.1[5:95MeOH/DCM] 580/582 151

R_(f) = 0.16[80:20EtOAc:Hex] 569/571 152

R_(f) = 0.3[10:90MeOH:DCM] 555/557 153

R_(f) = 0.25[10:90MeOH:DCM] 537/539 154

R_(f) = 0.2[5:95MeOH/DCM] 566/568 155

R_(f) = 0.1[50:50EtOAc:Hex] 484/486 156

R_(f) = 0.1[50:50EtOAc:Hex] 562/564 157

1.93 580 158

2.25 566 159

2.17 555 160

1.87 580 161

2.58 537 162

2.31 554 163

2.51 527 164

2.73 511 165

2.53 571 166

2.55 596 167

2.86 551 168

2.68 610 169

2.82 497 170

3.24 534 171

2.94 643 172

3.44 653 173

3.18 509 174

3.03 467 175

3.03 545 176

2.23 524 177

2.25 536 178

2.23 572 179

2.22 554 180

2.15 510 181

2.06 563 182

2.23 517 183

2.08 549 184

1.22 537 185

2.17 494 186

2.59 553 187

2.16 480 188

2.08 593 189

2.23 538 190

1.24 520 191

1.26 534 192

1.17 579 193

2.61 494 194

2.68 522 195

2.69 538 196

2.45 626 197

2.61 553 198

2.76 581 199

2.74 569 200

R_(f) = 0.25[5%MeOH/DCM] 589.2 201

3.09 376 202

R_(f) = 0.22[5%MeOH/DCM] 534 203

R_(f) = 0.69[10%MeOH/DCM] 456 204

R_(f) = 0.53[5%MeOH/DCM] 498 205

R_(f) = 0.55[15%MeOH/DCM] 513 206

R_(f) = 0.23[50%MeOH/DCM] 499 207

R_(f) = 0.14[20%MeOH/DCM] 552 208

R_(f) = 0.59[20%MeOH/DCM] 509 209

R_(f) = 0.51[20%MeOH INDCM] 568 210

R_(f) = 0.68[20%MeOH INDCM] 561 211

R_(f) = 0.24[20%MeOH INDCM] 552 212

R_(f) = 0.10[20%MeOH INDCM] 554 213

R_(f) = 0.44[2:1EtOAc/Hex] 489 214

R_(f) = 0.69[10%MeOH INDCM] 447 215

R_(f) = 0.42[EtOAc] 525 216

0.86 504 217

0.85 490 218

R_(f) = 0.76[20:80MeOH/DCM] 518 219

0.87 552 220

1.01 559 221

0.93 500 222

0.84 504 223

0.87 543 224

0.83 529 225

0.83 516 226

0.83 474 227

2.59 538 228

R_(f) = 0.25[20:80MeOH/DCM] 483 229

2.74 469 230

1.09 517 231

2.26 534 232

1.20 460 233

1.00 516 234

1.39 514 235

1.97 528 236

1.38 514 237

2.04 525 238

2.50 523 239

2.47 523 240

2.06 420 241

2.61 419 242

1.89 462 243

2.55 432 ^(a)Analytical HPLC were obtained using a Gilson HPLC equippedwith a quaternary pump, a variable wavelength detector set at 254 nm, aYMC pro C-18 column (50 × 4.6 mm, 12 μm). The eluents were A:acetonitrile w/0.1% TEA and B: H₂O w/0.1% TFA. Gradient elution from 10%B to 90% over 4 mm at a flowrate of 4.0 mL/min was used with an initialhold of 0.5 min and a final hold at 90% B of 0.5 minutes. Total run timewas 5 min.

The compound structures of Table 1 correspond to the IUPAC compoundnames in Table 2 below.

TABLE 2 Entry No. IUPAC Name 14-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 24-[(4-bromo-2-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 3N-(3-chloro-4-fluorophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 4N-(3-chloro-4-fluorophenyl)-7-(1-piperidinylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 5N-(3-chloro-4-fluorophenyl)-7-(4-morpholinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 6N-(4-bromo-2-fluorophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 7N-(4-bromo-2-fluorophenyl)-7-(1-piperidinylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 84-[(3-chloro-4-fluorophenyl)amino]-N-(2-methoxyethyl)-N-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide 9N-(4-bromo-2-fluorophenyl)-7-(4-morpholinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 104-[(4-bromo-2-fluorophenyl)amino]-N-(2-methoxyethyl)-N-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide 11N-(3-chloro-4-fluorophenyl)-7-{[(2-methoxyethyl)(methyl)amino]methyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 12N-(3-chloro-4-fluorophenyl)-7-(4-morpholinylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 13N-(3-chloro-4-fluorophenyl)-7-[(4-methyl-1-piperazinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 14 Ethyl4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate 15N-(3-chloro-4-fluorophenyl)-7-[(4-methyl-1-piperazinyl)methyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 164-[(3-chloro-4-fluorophenyl)amino]-N-(2-methoxyethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide 17N-(3-chloro-4-fluorophenyl)-7-{[(2-methoxyethyl)amino]methyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 18N-(3-bromophenyl)-7-(4-morpholinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 19N-(4-bromo-2-fluorophenyl)-7-[(4-methyl-piperazinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 204-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 214-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 22N-(3-bromophenyl)-7-[(4-methyl-1-piperazinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 234-[(4-bromo-2-fluorophenyl)amino]-N-(2-methoxyethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-carboxamide 24 ethyl4-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate 25N-(3-bromophenyl)-7-(4-morpholinylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 26N-(3-bromophenyl)-7-[(4-methyl-1-piperazinyl)methyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 27N-(3-bromophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 284-[(3-chloro-4-fluorophenyl)amino]-N-(3-methoxypropyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide 294-[(3-bromophenyl)amino]-N-(2-methoxyethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide 30N-(3-bromophenyl)-7-(1-piperidinylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 314-[(3-bromophenyl)amino]-N-(2-methoxyethyl)-N-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide 32 Ethyl4-{[4-(benzyloxy)phenyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate 33N-(3-chloro-4-fluorophenyl)-7-{[(3-methoxypropyl)amino]methyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 34N-(4-bromo-2-fluorophenyl)-7-{[(2-methoxyethyl)amino]methyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 35N-(4-bromo-2-fluorophenyl)-7-(4-morpholinylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 36N-(3-bromophenyl)-7-{[(2-methoxyethyl)(methyl)amino]methyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 37N-(3-bromophenyl)-7-{[(2-methoxyethyl)amino]methyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 38N-(3-bromophenyl)-7-({[2-(4-morpholinyl)ethyl]amino}methyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 39 Ethyl4-[(3-hydroxy-4-methylphenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate 40 Ethyl4-[(3-hydroxyphenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate 41 Ethyl4-[(2-fluoro-4-iodophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate 42 Ethyl4-[(4-chloro-2-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate 43N-[4-(benzyloxy)phenyl]-7-[(4-methyl-1-piperazinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 44 Ethyl4-[(2-fluoro-4-methylphenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate 45N-(3-bromophenyl)-7-[2-(4-morpholinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 464-[(3-hydroxy-4-methylphenyl)amino]-5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 474-[(3-hydroxyphenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 484-[4-({4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}carbonyl)-1-piperazinyl]benzonitrile 49N-(3-bromophenyl)-7-{[4-(4-methoxyphenyl)-1-piperazinyl]carbonyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 504-[(2-fluoro-4-iodophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 514-[(4-chloro-2-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 524-[(3-chloro-4-fluorophenyl)amino]-N-[2-(methylsulfonyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide 534-[(2-fluoro-4-methylphenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid 54N-(3-chloro-4-fluorophenyl)-7-[2-(4-morpholinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 55N-(3-chloro-4-fluorophenyl)-7-({[2-(methylsulfonyl)ethyl]amino}methyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 56N-allyl-4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide 57 ethyl{4-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetate 58N-(3-chloro-4-fluorophenyl)-7-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 59N-(3-chloro-4-fluorophenyl)-7-[2-(4-methyl-1-piperazinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 60N-(3-bromophenyl)-7-{[(3R)-3-(dimethylamino)-1-pyrrolidinyl]carbonyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 61N-(3-chloro-4-fluorophenyl)-7-[2-(4-morpholinyl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 622-{4-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}-N-(2-methoxyethyl)acetamide 63 Ethyl{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetate 642-{4-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethanol 65{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetic acid 66N-(3-bromophenyl)-7-{[(3R)-3-(dimethylamino)-1-pyrrolidinyl]methyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 67N-(3-chloro-4-fluorophenyl)-7-[2-oxo-2-(1-piperidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 68N-(3-bromophenyl)-7-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 692-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}-N-[3-(4-morpholinyl)propyl]acetamide 70N-(3-bromophenyl)-7-[2-(4-morpholinyl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 71N-(3-bromophenyl)-7-[2-oxo-2-(1-piperidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 724-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetic acid 73N-(3-chloro-4-fluorophenyl)-7-[2-(1-piperidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 74N-(3-chloro-4-fluorophenyl)-7-[2-(1-pyrrolidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 75N-(3-chloro-4-fluorophenyl)-7-{2-[(2-methoxyethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 76N-(3-chloro-4-fluorophenyl)-7-{2-[(4-methoxyphenyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 772-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}-N-[2-(methylsulfonyl)ethyl]acetamide 78N-(3-bromophenyl)-7-(2-{[2-(4-morpholinyl)ethyl]amino}ethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 79N-(3-bromophenyl)-7-[2-(1-piperidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 80N-(3-bromophenyl)-7-[2-(4-methyl-1-piperazinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 81N-(3-bromophenyl)-7-[2-oxo-2-(1-pyrrolidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 822-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}-N-(2-methoxyethyl)acetamide 832-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}-N-(2-methoxyethyl)-N-methylacetamide 84N-(3-bromophenyl)-7-(2-{[2-(methylsulfonyl)ethyl]amino}ethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 85N-(3-bromophenyl)-7-[2-(1-pyrrolidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 86N-(3-bromophenyl)-7-{2-[(2-methoxyethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 87N-(3-bromophenyl)-7-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 88N-(3-bromophenyl)-7-[2-(1H-emidazol-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 89N-(3-bromophenyl)-7-{2-[(4-methoxyphenyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 90N-(3-bromophenyl)-7-(2-methoxyethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 91N-(3-bromophenyl)-7-{2-[4-(2-methoxyethyl)-1-piperazinyl]-2-oxoethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 92N-(3-bromophenyl)-7-{2-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]-2-oxoethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 93N-(3-bromophenyl)-7-{2-[4-(2-methoxyethyl)-1-piperazinyl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 94N-(3-bromophenyl)-7-{2-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 951-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}-2-methyl-2-propanol 96N-(3-chloro-4-fluorophenyl)-7-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 97N-(3-chloro-4-fluorophenyl)-7-(2-{[(2-methylsulfonyl)ethyl]amino}ethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 98N¹-(2-{4-[(3-chloro-4-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethyl)-N²,N²-dimethyl-1,2-ethanediamine 99N-(3-chloro-4-fluorophenyl)-7-{2-[4-(4-pyridinylmethyl)-1-piperazinyl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 100 N-(3-chloro-4-fluorophenyl)-7-{2-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 101 N-(3-chloro-4-fluorophenyl)-7-(2-methoxyethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1022-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethanol 103N-(3-bromophenyl)-7-{2-oxo-2-[4-(4-pyridinylmethyl)-1-piperazinyl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 104N-{7-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl}-N-(3,4,5-trimethoxyphenyl)amine 105N-(4-bromo-2-fluorophenyl)-7-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 106N-(2-{4-[(3-chlorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethyl)-2-thiophenesulfonamide 107N-({4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methyl)-N,N-diethylurea 108N-({4-[(3-ethynylphenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methyl)-N′-(3-pyridinyl)urea 109N-({4-[(3-chloro-4-fluoropheny)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methyl)-N′-ethylurea 110N-(4-methoxyphenyl)-N′-({4-[(3-methoxyphenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methyl)urea 111N-(2-{4-[(2,4-dichlorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethyl)-1-pyrrolidinecarboxamide 112N-({4-[(3-phenoxyphenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}methyl)-4-morpholinecarboxamide 1134-[(3-chloro-4-fluorophenyl)amino]-N-(3-methoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide 114[1-({4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}carbonyl)-2-pyrrolidinyl]methanol 115N-(3-chloro-4-fluorophenyl)-7-[(2,5-dimethyl-1-pyrrolidinyl)carbonyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 116N-(3-chlorophenyl)-7-{[2-(methoxymethyl)-1-pyrrolidinyl]carbonyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1171-({4-[(4-bromo-2-fluorophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetyl)-3-pyrrolidinol 118N-(3-bromophenyl)-7-[2-(3-methyl-1-pyrrolidinyl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 119N-(3-ethynylphenyl)-7-(4-thiomorpholinylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 120N-(4-bromo-2-fluorophenyl)-7-{[2-(methoxymethyl)-1-pyrrolidinyl]methyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 121N-(3-chloro-4-fluorophenyl)-7-{2-[4-(3-methylphenyl)-1-piperazinyl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 122N-(3-chloro-2-fluorophenyl)-7-(2-pyrrolidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 123N-{7-[2-(2,5-dimethylpyrrolidin-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl}benzene-1,3-diamine 124N-(2-fluorophenyl)-7-(2-oxo-2-pyrrolidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1252-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}-N-[3-(ethylamino)phenyl]acetamide 1267-allyl-N-(3-ethynylphenyl)-7-(pyrrolidin-1-ylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1277-benzyl-N-(3,4-dichlorophenyl)-7-({[2-(methylsulfonyl)ethyl]amino}methyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 128N-(3-chloro-4-fluorophenyl)-7-methyl-7-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 129 ethyl[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]acetate 1302-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethanol 1317-(2-bromoethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 132N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 133N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 134N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 135N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-{2-[(2-methoxyethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 136 ethyl[4-({3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]acetate 137N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-(2-morpholin-4-yl-2-oxoethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 138N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1392-[4-({3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]-N-(2-methoxyethyl)acetamide 1402-[4-({3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]-N-[2-(methylsulfonyl)ethyl]acetamide 141N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-2-oxoethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 142N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-(2-oxo-2-pyrrolidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 143N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1442-[4-({3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]-N-(2-methoxyethyl)-N-methylacetamide 145 N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 146N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-(2-pyrrolidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 147N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-[2-(4-methylpiperazin-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1482-[4-({3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethanol 1492-[4-({3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl methanesulfonate 150N-{3-chloro-4-[(4-fluorobenzyl)oxy]phenyl}-7-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 151N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-[2-(4-methylpiperazin-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 152N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 153N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-{2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 154N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-(2-pyrrolidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 155N′-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}-N,N-dimethylethane-1,2-diamine 1562-({2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}amino)ethanol 157N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1582,2′-({2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}imino)diethanol 159N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-{2-[(2-morpholin-4-ylethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 160N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-(2-piperidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 161N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 162N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-[2-(methylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 163N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-[2-(1H-imidazol-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 164N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-{2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1654-(4-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}piperazin-1-yl)benzonitrile 166 ethyl(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)acetate 1672-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)ethanol 1682-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)ethyl methanesulfonate 169N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-{2-[(2-methoxyethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 170N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 171N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-(2-{[2-(methylsulfonyl)ethyl]amino}ethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1722,2′-{[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)ethyl]imino}diethanol 1732-{[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)ethyl]amino}ethanol 174N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-{2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 175N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-[2-(1H-imidazol-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 176N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-[2-(4-methylpiperazin-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 177N′-[2-(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)ethyl]-N,N-dimethylethane-1,2-diamine 178N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 179(3S)-1-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}pyrrolidin-3-ol 180N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-[2-(methylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 181N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-{2-[4-(2-methoxyethyl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 182N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 183N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-(2-pyrrolidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 184N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-(2-piperidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 185N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-{2-[(2-morpholin-4-ylethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 186N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-[2-(ethylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 187N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-[2-(diethylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 188N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-{2-[(3-methoxypropyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 189N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-7-{2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 190(3R)-1-{2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}pyrrolidin-3-ol 191N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-{2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 192N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-(2-thiomorpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 193N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-(2-{[2-(methylsulfonyl)ethyl]amino}ethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1944-[(3-chloro-4-fluorophenyl)amino]-7-vinyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-ol 1952-{4-[(1-benzyl-1H-indazol-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethyl methanesulfonate 1962-{4-[(1-benzyl-1H-indazol-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethanol 197 ethyl{4-[(1-benzyl-1H-indazol-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetate 198N-(1-benzyl-1H-indazol-5-yl)-7-{2-[(2-methoxyethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 1992-[(2-{4-[(1-benzyl-1H-indazol-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethyl)amino]ethanol 200N-(1-benzyl-1H-indazol-5-yl)-7-{2-[3-(dimethylamino)pyrrolidin-1-yl]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 201N-(1-benzyl-1H-indazol-5-yl)-7-(2-pyrrolidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 202N-(1-benzyl-1H-indazol-5-yl)-7-{2-[(2-morpholin-4-ylethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 203N-(1-benzyl-1H-indazol-5-yl)-7-(2-{[2-(methylsulfonyl)ethyl]amino}ethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 204N-(1-benzyl-1H-indazol-5-yl)-7-{2-[(2-pyrrolidin-1-ylethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 205N′-(2-{4-[(1-benzyl-1H-indazol-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethyl)-N,N-dimethylbutane-1,4-diamine 206 ethyl[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]acetate 2072-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethanol 2082-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl methanesulfonate 2097-{2-[(2-methoxyethyl)amino]ethyl}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine2102-({2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}amino)ethanol 2117-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 212N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-7-(2-{[2-(methylsulfonyl)ethyl]amino}ethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 213N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-7-{2-[(2-morpholin-4-ylethyl)amino]ethyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 214N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-7-(2-pyrrolidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 2152-(methyl{2-(4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}amino)ethanol216 7-{2-[3-(dimethylamino)pyrrolidin-1-yl]ethyl}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 217N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-7-[2-(4-methylpiperazin-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 218N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-7-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 2197-[2-dimethylamino)ethyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine220N-(1-benzyl-1H-indazol-5-yl)-7-[2-(4-methylpiperazin-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 221N-(1-benzyl-1H-indazol-5-yl)-7-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 222N-(1-benzyl-1H-indazol-5-yl)-7-[2-(methylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 223N,N-dimethyl-N′-{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}ethane-1,2-diamine 2242,2′-({2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}imino)diethanol 2257-[2-(methylamino)ethyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine2261-{2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl]ethyl}pyrrolidin-3-ol 227N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-7-[2-(2-methylpyrrolidin-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 2287-[2-(2,5-dimethylpyrrolidin-1-yl)ethyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine229N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-7-(2-piperidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 2301-(2-{4-[(1-benzyl-1H-indazol-5-yl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethyl)pyrrolidin-3-ol 231N-(1-benzyl-1H-indazol-5-yl)-7-[2-(2-methylpyrrolidin-1-yl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 232N-(1-benzyl-1H-indazol-5-yl)-7-(2-piperidin-1-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 233N-(3-chloro-4-fluorophenyl)-N-7-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4,7-diamine 234N-(3-chloro-4-fluorophenyl)-7-morpholin-4-yl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine 235N-(3-chloro-4-fluorophenyl)-N-7-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4,7-diamine 236N-(3-chloro-4-fluorophenyl)-7-(4-methylpiperazin-1-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

Asymmetry, i.e., where a compound's mirror image cannot be super-imposedon the compound, may be present in a compound of Formula I due to theinherent structure of the molecule. Examples of such asymmetricmolecules include certain allenes. The compounds of this invention mayalso contain one or more asymmetric centers, depending upon the locationand nature of the various substituents selected. A molecule with asingle asymmetric center may be a mixture of enantiomers (R,S), or maybe a single (R) or (S) enantiomer. A molecule with more than oneasymmetric center may be a mixture of diastereomers, or may be a singlediastereomer. Additionally, a compound may exhibit asymmetry due torestricted rotation about a given bond, for example, the central bondadjoining two substituted aromatic rings of the specified compounds. Itis intended that all such configurations and conformations (includingenantiomers, diastereomers, and other optical isomers) are includedwithin the scope of the present invention. Separated, pure or partiallypurified stereoisomers of the compounds of Formula I are each includedwithin the scope of the present invention. Preferred compounds are thosewith the absolute configuration or conformation which produces the moredesirable biological activity.

Pharmaceutically acceptable salts of the compounds of this invention arealso within the scope of this invention. The term “pharmaceuticallyacceptable salt” refers to an inorganic or organic salt of a compound ofthe present invention that has properties acceptable for therapeuticuse. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J.Pharm. Sci. 1977, 66, 1–19.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts that areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, sulfate, and undecanoate. The term acidaddition salts also comprises the hydrates and the solvent additionforms which the compounds of this invention are able to form. Examplesof such forms are, for example, hydrates, alcoholates and the like.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glucamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates including dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides includingbenzyl and phenethyl bromides, and others.

The esters of appropriate compounds of this invention arepharmaceutically acceptable esters such as (C₁–C₆)alkyl esters,including methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentylesters, and the like. Additional esters such as (C₁–C₆)alkyl-phenyl maybe used, although methyl ester is preferred.

Unless the context clearly indicates to the contrary, whenever the term“compounds of this invention,” “a compound of the present invention”,and the like, are used herein, they are intended to include thechemically feasible pharmaceutically acceptable salts and/or esters aswell as all stereoisomeric forms of the referenced compounds.

Method of Making the Compounds of the Present Invention

In general, the compounds used in this invention may be prepared bystandard techniques known in the art, by known processes analogousthereto, and/or by the processes described herein, using startingmaterials which are either commercially available or producibleaccording to routine, conventional chemical methods.

Generic Schemes

The following Reaction Schemes 1–4 illustrate a preferred syntheticroute for synthesizing the compounds of Formula I.

Reaction Scheme 1 depicts the synthesis of the compounds of Formula I.

The cyclohexanone (1) of Reaction Scheme I, where each R of (R)₂ may bethe same or may be different, (that is, one R may be H and the other Ris other than H, or both R's may be other than H where each R is thesame or different), is commercially available or may be preparedaccording to one of the following schemes: Jaen et al, Bio. Org. Med.Chem. Lett., 1993, 3 (4), 639–644, Tetrahedron 1997, 53 (13),4693–4702.; Tetrahedron: Asym. 1994, 5 (3), 339–342.; Tetrahedron: Asym.1995, 6 (11), 2647–2650.; Aust. J. Chem. 1994, 47(10), 1833–1842.;Tetrahedron 1999, 55, 11095–11108.), each of which is incorporatedherein by reference. Cyclohexanone (1) is coupled with an appropriatecyanoacetic ester (2) in the presence of elemental sulfur and a basesuch as morpholine, preferably at room temperature, to yield theaminothiophene ester of formula (3) according to the procedure ofGewald, J. Heterocyclic Chem., 1999, 36, 333–345, which is incorporatedherein by reference. The aminothiophene ester (3) is then converted to acompound of formula (4) by reaction with a formamide-containing reagentsuch as neat formamide, or formamidine acetate, in a polar solvent suchas DMF, with heat, preferably to 100° C. or above. Heating the compoundof formula (4) with a reagent such as phosphorous oxychloride providescompound (5). Finally, compound (5) may be reacted with a variety ofsubstituted anilines (6), each of which is readily available or can besynthesized by means well known in the art, in the presence of acatalytic amount of concentrated acid, such as HCl, and a proticsolvent, such as ethanol, to yield a compound of Formula I.

Reaction Scheme 2 outlines the synthesis of certain compounds of FormulaI where one R is H (not shown) and the other R is (C₁–C₆)alkylsubstituted with OH or halo, or with C(O)R⁶ where R⁶ is NR⁸R⁸.

The starting material (Ia), where one R is H (not shown) and the other Ris (CH₂)_(m)C(O)O(C₁–C₃)alkoxy, and m is 0, 1, 2, 3, 4, 5 or 6 may bemade according to Reaction Scheme 1. Compound (Ia) is either saponifiedto its corresponding carboxylic acid under basic conditions (such as 1NNaOH in an appropriate solvent) and subsequently coupled with1,1′-carbonyldiimidazole and an amine (HNR⁸R⁸) to yield the amide (Ib),or alternatively, (Ia) is converted to the amide (Ib) by a Weinreb(Tetrahedron Lett. 1981, 22 (39), 3815–3818) amidation with a reagentsuch as trimethyl aluminum and a nucleophilic amine such as piperidine(as shown in Example 3). If desired, (Ib) is reduced to itscorresponding amine (Ie) in one step via a reducing reagent such asDIBAL-H in a protic solvent such as THF. Compound (Ia) may also bereduced to its corresponding alcohol (Ic) with a reducing agent such asDIBAL-H in a protic solvent such as THF. The alcohol (Ic) may be furthertransformed into the bromoalkyl (Id) by bromination with a reagent suchas CBr₄ in the presence of PPh₃. Reaction of the bromoalkyl (Id) with anamine (NHR⁸R⁸) such as piperidine (such as in Example 4) also yieldscompounds of formula (Ie).

Reaction Scheme 3 outlines the synthesis of the compounds of Formula Iwhere one R is H (not shown) and the other R is (C₁–C₆)alkyl R⁷ and R⁷is NH S(O)₂R⁹ (If), or NH(C(O)NR⁸R⁸ (Ig).

Compound (Ie′) (where R⁸ of (Ie)'s NR⁸R⁸ group is H in both instances)of Reaction Scheme 2 is reacted with an amine HNR⁸R⁸ in the presence ofa coupling reagent such as 1,1′-carbonyldiimidazole, or (Ie) is reactedwith an isocyanate R⁸N═C═O. Compounds of formula (Ie) can also bereacted with sulfonyl chlorides and a mild base such as TEA in a solventsuch as CH₂Cl₂ to yield the compounds of Formula (Ig).

Reaction Scheme 4 outlines the synthesis of the compounds of Formula(Ih), and of Formula (Ii) where one R is H (not shown) and the other Ris (CH₂)_(m)C(O)R⁶, m is 0, 1, 2, 3, 4, 5 or 6, and R⁶ is (C₁–C₆)alkyl,pyridyl or phenyl.

In one pathway of Reaction Scheme 4, the compound of formula (Ia), aspreviously described above in Reaction Scheme 2, is reacted in an inertsolvent such as THF, with an alkyl or aryl Grignard reagent of formulaR⁶MgX, where R⁶ is a (C₁–C₆)alkyl, phenyl or pyridyl group and X is Br,Cl, or I, to provide a ketone of formula (Ii). In the alternativepathway, the formula (Ia) compound is first saponified to thecorresponding carboxylic acid, the convert to an acid chloride offormula (Ih), which is then subjected to the same Grignard reactionconditions to provide compound (Ii).

The following specific examples are presented to aid the reader in thesynthesis of the compounds of the present invention, but are notintended to limit the scope of the invention in any way.

Abbreviations and Acronyms

When the following abbreviations are used throughout the disclosure,they have the following meaning:

-   ACN acetonitrile-   anhyd anhydrous-   CDCl₃-d chloroform-d-   CD₂Cl₂-d₄ methylene chloride-d₄-   CDl 1,1′-dicarbonyldimidazole-   Celite® registered trademark of Celite Corp. brand of diatomaceous    earth-   DIBAL-H diisobutylaluminum hydride-   DMF N,N-dimethyl formamide-   DMSO-d₆ dimethylsulfoxide-d₆-   EtOAc ethyl acetate-   equiv equivalent(s)-   h hour(s)-   ¹H NMR proton nuclear magnetic resonance-   HCl hydrochloric acid-   Hex hexanes-   HPLC high performance liquid chromatography-   LCMS liquid chromatography/mass spectroscopy-   LiH lithium hydride-   MeOH methanol-   min minute(s)-   MS mass spectrometry-   Pd/C palladium on carbon-   R_(f) TLC retention factor-   Rochelle's salt sodium potassium tartrate-   rt room temperature-   RT retention time (HPLC)-   satd saturated-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography    General Analytical Procedures

The structure of representative compounds of this invention wereconfirmed using the following procedures.

Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard 5989A mass spectrometer equipped with a Hewlett Packard 5890 GasChromatograph with a J & W DB-5 column (0.25 uM coating; 30 m×0.25 mm).The ion source is maintained at 250° C. and spectra were scanned from50–800 amu at 2 sec per scan.

High pressure liquid chromatography-electrospray mass spectra (LC-MS)were obtained using either a:

-   (A) Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a    variable wavelength detector set at 254 nm, a YMC pro C-18 column    (2×23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometer with    electrospray ionization. Spectra were scanned from 120–1200 amu    using a variable ion time according to the number of ions in the    source. The eluents were A: 2% acetonitrile in water with 0.02% TFA    and B: 2% water in acetonitrile with 0.018% TFA. Gradient elution    from 10% B to 95% over 3.5 minutes at a flowrate of 1.0 mL/min is    used with an initial hold of 0.5 minutes and a final hold at 95% B    of 0.5 minutes. Total run time is 6.5 minutes. or-   (B) Gilson HPLC system equipped with two Gilson 306 pumps, a Gilson    215 Autosampler, a Gilson diode array detector, a YMC Pro C-18    column (2×23 mm, 120 A), and a Micromass LCZ single quadrupole mass    spectrometer with z-spray electrospray ionization. Spectra were    scanned from 120–800 amu over 1.5 seconds. ELSD (Evaporative Light    Scattering Detector) data is also acquired as an analog channel. The    eluents were A: 2% acetonitrile in water with 0.02% TFA and B: 2%    water in acetonitrile with 0.018% TFA. Gradient elution from 10% B    to 90% over 3.5 minutes at a flowrate of 1.5 mL/min is used with an    initial hold of 0.5 minutes and a final hold at 90% B of 0.5    minutes. Total run time is 4.8 minutes. An extra switching valve is    used for column switching and regeneration.

Routine one-dimensional NMR spectroscopy is performed on 300 MHz VarianMercury-plus spectrometers. The samples were dissolved in deuteratedsolvents obtained from Cambridge Isotope Labs, and transferred to 5 mmID Wilmad NMR tubes. The spectra were acquired at 293 K. The chemicalshifts were recorded on the ppm scale and were referenced to theappropriate solvent signals, such as 2.49 ppm for DMSO-d₆, 1.93 ppm forCD₃CN-d₃, 3.30 ppm for CD₃OD-d₄, 5.32 ppm for CD₂Cl₂-d₄ and 7.26 ppm forCDCl₃-d for ¹H spectra.

EXAMPLE 1 Preparation of4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylicacid

In a 15 mL round-bottom flask were placed 100 mg (0.23 mmol, 1 equiv) ofethyl4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylatein 3 mL of methanol and 1.5 mL of THF. The mixture was stirred until allsolids dissolved and then 0.93 mL (0.93 mmol, 4 equiv) of 1N NaOH wasadded. The reaction was allowed to stir at rt for 16 h and then organicsolvents were concentrated in vacuo. The resulting residue wasre-dissolved in H₂O (10 mL) and the solution was acidified to pH 5 with1N HCl. Once the solution was slightly acidic a white solidprecipitated; the precipitate was filtered and washed with water (15 mL)and dried in a hi-vac oven overnight to provide 80 mg (87%) of thedesired product, 1, as a pure white solid. ¹H-NMR (DMSO-d₆) δ 12.20 (s,1H), 8.42 (s, 1H), 8.42 (s, 1H), 7.95 (t, 1H), 7.67–7.64 (m, 1H),7.30–7.21 (m, 2H), 3.25–2.81 (m, 5H), 2.34–2.18 (m, 1H), 1.83–1.97 (m,1H); LCMS RT=2.94 min; [M+H]⁺=406.2.

Using the method described above and the appropriate starting materials,Examples 2, 20, 46–47, 50–51 and 53 were similarly prepared.

EXAMPLE 14 Preparation of ethyl4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate

Step 1. Preparation of Example 14: diethyl2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3,6-dicarboxylate

In a 200 mL round-bottom flask were placed 2.0 g (11.75 mmol, 1 equiv)of ethyl cyclohexanone-4-carboxylate, 1.3 g (11.75 mmol, 1 equiv) ofethyl cyanoacetate, 1.02 mL (11.75 mmol, 1 equiv) of morpholine, 376 mg(11.75 mmol, 1 equiv) of elemental sulfur and ethanol (50 mL). Themixture was stirred at rt for 4 days until all sulfur was dissolved. Themixture was concentrated then re-dissolved in EtOAc (75 mL) and pouredinto a separatory funnel. The organic layer was washed with water (2×75mL) then dried (MgSO₄), filtered, and evaporated. The desired productwas obtained in quantitative yield (3.5 g) as a yellow solid and used infurther reactions without further purification. ¹H-NMR (CDCl₃-d) δ 4.25(q, 2H), 4.14 (q, 2H), 2.93 (m,1H), 2.68 (m, 4H), 2.18 (m, 1H), 2.05 (s,2H), 1.81 (m, 1H), 1.34 (t, 3H), 1.28 (t, 3H). LCMS RT=3.49 min;[M+H]⁺=297.

Step 2. Preparation of Example 14: Ethyl4-oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate

In a 100 mL round-bottom flask was placed 3.5 g (11.75 mmol, 1 equiv) of2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3,6-dicarboxylic aciddiethyl ester in 10 mL of formamide. The flask was equipped with areflux condenser and heated at 140° C. for 16 h. The mixture was thenallowed to cool to rt and a brown solid precipitated from solution. Theresulting precipitate was filtered and rinsed with EtOAc (200 mL) anddried in a hi-vac oven for 2 h. After drying 3.25 g (99%) of the desiredproduct as a brown solid was obtained and used without furtherpurification in the next step. LCMS RT=2.80 min; [M+H]⁺=279.

Step 3. Preparation of Example 14: ethyl4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate

In a 150 mL round-bottom flask was placed 3.0 g (10.78 mmol, 1 equiv) of4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-7-carboxylicacid ethyl ester in 60 mL of phosphorous oxychloride. The flask wasequipped with a reflux condenser and heated at 80° C. for 2 h. Thereaction mixture was cooled to rt and excess phosphorous oxychloride wasconcentrated in vacuo. Toluene (50 mL) was added to residue and onceagain concentrated to eliminate remaining POCl₃. The resulting cruderesidue was quenched with ice/water and a solid precipitates fromsolution. The precipitate was filtered, rinsed with water (100 mL) anddried in a hi-vac oven for 48 h to provide 2.47 g (77%) of the desiredproduct as a light yellow solid. ¹H-NMR (CDCl₃-d) δ 8.75 (s, 1H), 4.21(q, 2H), 3.11 (m, 4H), 2.91 (m, 1H), 2.37 (m, 1H), 2.05 (m, 1H), 1.25(t, 3H), 7.36 (t, 1H), 7.35 (t, 1H), 7.20 (t, 1H), 7.02 (t, 1H); LCMSRT=3.04 min; [M+H]⁺=297.

Step 4. Preparation of Example 14: ethyl4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate

In a 25 mL round-bottom flask were placed 250 mg (0.84 mmol, 1.1 equiv)of4-chloro-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-7-carboxylicacid ethyl ester and 131 mg (0.77 mmol, 1 equiv) m-bromoaniline in 10 mLof ethanol with one drop conc HCl. The flask was equipped with a refluxcondenser and heated at 70° C. for 4 h. The mixture was allowed to coolto rt and ethanol was concentrated in vacuo. The resulting crude residuewas re-dissolved in EtOAc (10 mL), poured into a separatory funnel andwashed with satd NaHCO₃ (1×10 mL). The organic layer was dried (MgSO₄),filtered and concentrated to give a crude oil. The crude material wasfurther purified by MPLC (Biotage) using 1/4 EtOAc/Hex to provide 257 mg(77%) of the desired product, 14, as a white powder. ¹H-NMR (CDCl₃-d) δ8.44 (s, 1H), 7.92 (s, 1H), 7.55 (m, 1H), 7.23 (m, 2H), 7.08 (s, 1H),4.22 (q, 2H), 3.14 (m, 4H), 2.91 (m, 1H), 2.39 (m, 1H), 2.14 (m, 1H),1.30 (t, 3H); LCMS RT=3.48 min; [M+H]⁺=432.

Using the method described above and the appropriate starting materials,Examples 24, 32, 39–42, and 44 were similarly prepared.

EXAMPLE 27 Preparation ofN-(3-bromophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

Anhydrous toluene (2 mL) was added to a 50 mL round bottom flaskpreviously evacuated and refilled with argon or nitrogen gas (3×). Thiswas cooled to 0° C. in an ice-water bath for 5 min. Trimethylaluminum,0.2 mL (1.8 equiv, 2.0M solution in hexanes) was added and the reactionwas stirred at 0° C. for 15 min before piperidine (1.1 equiv, 0.25 mmol)was added to the above solution. It was allowed to stir at 0° C. for 10min before warming to rt for 20 min. A 3 mL toluene solution of 100 mg(0.23 mmol, 1 equiv) of ethyl4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate,14, was added and the reaction mixture was heated at 100° C. untilreaction was complete by TLC. The reaction mixture was cooled to 0° C.and quenched with 1N HCl. The reaction was adjusted to pH 9.0 with 1NNaOH and extracted with EtOAc (3×5 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated to give a crude oil which was purifiedvia flash column chromatography MeOH/CH₂Cl₂ 1:9 to provide the requiredproduct, 27, as a white solid (100 mg, 92%). ¹H-NMR (CD₂Cl₂-d₄) δ 8.49(s, 1H), 8.05 (d, 1H), 7.62–7.59 (m, 1H), 7.23–7.26 (m, 2H), 7.12 (s,1H), 3.59 (q, 2H), 3.52 (t, 2H), 3.23–3.10 (m, 3H), 2.94 (dd, 1H),2.20–2.19 (m, 1H), 2.10–2.08 (m, 1H), 1.71–1.58 (m, 7H); LCMS RT=3.28min; [M+H]⁺=473.3.

EXAMPLE 30 Preparation ofN-(3-bromophenyl)-7-(1-piperidinylmethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

Anhydrous THF (3 mL) was added to a 50 mL round bottom flask followed byN-(3-bromophenyl)-7-(1-piperidinylcarbonyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine(27, 0.21 mmol, 1equiv). This was cooled to 0° C. in an ice-water bathfor 5 min. Diisobutylaluminum hydride, 0.6 mL (DIBAL-H, 0.64 mmol, 1.0Min THF) was added and the reaction was stirred at 0° C. for 30 minbefore warming to rt for 2 h until reaction was complete by TLC. Thereaction mixture was quenched with a satd solution of Rochelle's salt (3mL) followed by water (3 mL). The reaction was extracted with EtOAc(3×10 mL). The organic layer was dried over anhyd Na₂SO₄ andconcentrated to give a crude oil which was purified via flash columnchromatography MeOH/CH₂Cl₂ 1:9 w/0.5% NH₄OH to provide the requiredproduct, 30, as an oil (70 mg, 72%). ¹H-NMR (CD₂Cl₂-d₄) δ 8.36 (s, 1H),7.94 (t, 1H), 7.50–7.47 (m, 1H), 7.15–7.13 (m, 2H), 7.10 (s, 1H),2.95–2.91 (m, 3H), 2.29–2.05 (m, 7H), 1.52–1.47 (m, 5H), 1.36 (t, 1H);LCMS RT=2.36 min; [M+H]⁺=459.2.

Using the method described above and the appropriate starting materials,Examples 4, 7, 11–12, 15, 17, 22, 25–26, 30, 33–38, 55 and 66 weresimilarly prepared.

EXAMPLE 56 Preparation ofN-allyl-4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxamide

To a 15 mL round-bottom flask were added 50 mg (0.124 mmol, 1 equiv) of4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylicacid, 1, 20 mg (0.124 mmol, 1 equiv) of CDl and THF (1.25 mL). Thereaction was stirred for 4 h at rt and then 0.01 mL (0.186 mmol, 1.5equiv) of allyl amine was added via syringe and the reaction was allowedto stir at rt overnight. The reaction was stopped and THF wasconcentrated in vacuo and the crude solid was re-dissolved in CH₂Cl₂ (5mL). This solution was poured into a separatory funnel and washed withsatd NaHCO₃ (1×5 mL), water (1×5 mL), and brine (1×5 mL). The organiclayer was dried (MgSO₄), filtered and concentrated to yield a whitesolid. The compound was triturated with diethyl ether to yield purematerial, 56, as a white solid (36 mg, 66%). ¹H-NMR (DMSO-d₆) δ 8.42 (s,1H), 8.31 (s, 1H), 8.19 (t, 1H), 7.86 (m, 1H), 7.63 (m, 1H), 7.25 (m,2H), 5.82 (m, 1H), 5.08 (m, 2H), 3.75 (t, 2H), 3.21 (m, 2H), 2.97 (d,2H), 2.69 (m, 1H), 2.15 (m, 1H), 1.82 (m, 1H); LCMS RT=2.78 min;[M+H]⁺=444.

Using the methods described above in Examples 27 and 56 and theappropriate starting materials, Examples 18–19, 21, 23, 27–29, 31, 43,48–49, 52, 56 and 60 were similarly prepared.

EXAMPLE 63 Preparation of ethyl{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetate

Step 1. Preparation of Example 63: ethyl1,4-dioxaspiro[4,5]dec-8-ylideneacetate

To a solution of THF (18 mL) under argon was added 0.38 g (47.8 mmol, 5equiv) of LiH, followed by slow addition of 8.78 g (47.8 mmol, 5 equiv)of triethyl phosphonoacetate. The solution was stirred at rt for 1 h and1.49 g (9.6 mmol, 1 equiv) of 1,4-cyclohexanedione mono-ethylene ketalwas added and the solution was heated at 65° C. for 16 h. Upon coolingthe solution was treated with MeOH (10 mL) and water (5 mL) andconcentrated in vacuo. The resulting yellow oil was purified by silicagel chromatography eluting with 4:1 Hex/EtOAc to yield 1.89 g (93%) of aclear oil. ¹H-NMR (CDCl₃-d) δ 5.67 (s, 1H), 4.16 (t, 2H), 3.99 (m, 4H),3.02 (m, 2H), 2.39 (m, 2H), 1.78 (m, 4H), 1.29 (t, 3H); LCMS RT=2.56min; [M+H]⁺=226.9.

Step 2. Preparation of Example 63: ethyl1,4-dioxaspiro[4,5]dec-8-ylacetate

To a solution of EtOH (100 mL) was added 182 mg (10% by weight) Pd/cunder argon. As a solution in EtOH, 1.82 g (8.0 mmol, 1 equiv) ethyl1,4-dioxaspiro[4,5]dec-8-ylideneacetate was added via syringe. The flaskwas charged with hydrogen (3×) and left stirring for 16 h. The flask wasevacuated and charged with argon (3×) and the solution was filteredthrough a pad of Celite® washing with EtOH (200 mL). The solution wasevaporated under reduced pressure yielding 1.74 g (95%) of a clear oil.¹H-NMR (CDCl₃-d) δ 4.13 (q, 2H), 3.95 (m, 4H), 2.24 (m, 2H), 1.96(m,1H), 1.75 (m, 4H), 1.58 (m, 2H), 1.31 (m, 2H), 1.27 (t, 3H); TLCR_(f)=0.20 (1:9 EtOAc/Hex).

Step 3. Preparation of Example 63: ethyl (4-oxocyclohexyl)acetate

To a solution of acetone (720 mL) was added 10 g (43.8 mmol, 1 equiv) ofethyl 1,4-dioxaspiro[4,5]dec-ylacetate followed by 1 N Hydrochloric acid(180 mL) The reaction was heated at reflux for 2 h. Upon cooling thesolution was diluted with EtOAc (100 mL) and washed with water (100 mL).The water layer was back extracted twice with EtOAc (100 mL) and theorganic layers were combined, dried (MgSO₄), filtered and concentratedto yield 7.57 g (94%) of a clear oil. ¹H-NMR (CDCl₃-d) δ 4.16 (q, 2H),2.40 (m, 4H), 2.32 (m, 2H), 2.28 (m, 1H), 2.10 (m, 2H), 1.49 (m, 2H),1.28 (t, 3H); TLC R_(f)=0.32 (3:7 EtOAc/Hex).

Step 4. Preparation of Example 63: ethyl2-amino-6-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate

The compound was prepared as described in Example 14, Step 1.

¹H-NMR (CDCl₃-d) δ 5.96 (s, 2H), 4.25 (q, 2H), 4.15 (q, 2H), 2.87 (m,1H), 2.65 (m, 2H), 2.32 (m, 4H), 1.91 (m, 1H), 1.46 (m, 1H), 1.34 (t,3H), 1.28 (t, 3H); LCMS RT=3.17 min; [M+H]⁺=312.0.

Step 5. Preparation of Example 63: ethyl(4-oxo-3,4,5,6,7,8-hexahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)acetate

The compound was prepared as described in Example 14, Step 2.

¹H-NMR (DMSO-d₆) δ 12.31 (s, 1H), 7.99 (s, 1H), 4.09 (q, 2H), 3.06 (m,1H), 2.87 (m, 1H), 2.75 (m, 1H), 2.40 (m, 3H), 2.19 (m, 1H), 1.89 (m,1H), 1.47 (m, 1H), 1.19 (t, 3H); LCMS RT=2.40 min; [M+H]⁺=293.1.

Step 6. Preparation of Example 63: ethyl(4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl)acetate

The compound was prepared as described in Example 14, Step 3.

¹H-NMR (CDCl₃-d) δ 8.72 (s, 1H), 4.19 (q, 2H), 3.31 (m, 1H), 3.07 (m,2H), 2.65 (m, 1H), 2.46 (m, 3H), 2.12 (m, 1H), 1.65 (m, 1H), 1.31 (t,3H); LCMS RT=3.70 min; [M+H]⁺=311.2.

Step 7. Preparation of Example 63: ethyl{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetate

The compound was prepared as described in Example 14, Step 4.

¹H-NMR (CD₂Cl₂-d₄) δ 8.47 (s, 1H), 8.06–8.04 (m, 1H), 7.60–7.57 (m, 1H),7.26–7.24 (m, 2H), 7.16 (s, 1H), 4.17 (q, 2H), 3.16–3.02 (m, 3H),2.67–2.59 (m, 1H), 2.46 (s, 3H), 2.21–2.16 (m, 1H), 1.76–1.69 (m, 1H),1.30 (t, 3H); LCMS RT=4.00 min; [M+H]⁺=448.2.

Using the method described above and the appropriate starting materials,Example 57 was similarly prepared.

EXAMPLE 65 Preparation of{4-[(3-bromophenyl)amino]-5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}aceticacid

The compound was prepared as described in Example 1.

¹H-NMR (CD₃OD-d₄) δ 8.51 (s, 1H), 7.88 (s, 1H), 7.57–7.36 (m, 3H),3.26–3.10 (m, 2H), 2.72–2.65 (m, 1H), 2.48 (s, 3H), 2.24–2.16 (m, 1H),1.76–1.68 (m, 1H); LCMS RT=3.48 min; [M+H]⁺=420.2.

Using the method described above and the appropriate starting materials,Example 72 was similarly prepared.

EXAMPLE 70 Preparation ofN-3-bromophenyl)-7-[2-(4-morpholinyl)-2-oxoethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

The compound was prepared as described in Example 27. ¹H-NMR (CD₂Cl₂-d₄)δ 8.36 (s, 1H), 7.95 (t, 1H), 7.49–7.46 (m, 1H), 7.15–7.13 (m, 2H), 7.10(s, 1H), 3.57–3.49 (m, 9H), 3.38–3.34 (m, 2H), 3.04–2.95 (m, 4H),2.50–2.46 (m, 1H), 2.36–2.32 (m, 3H), 2.13–2.05 (m, 1H), 1.66–1.56 (m,1H); LCMS RT=2.91 min; [M+H]⁺=487.4.

Using the method described above and the appropriate starting materials,Examples 58, 61–62, 67–71, 77, 81–83, 91–92 and 103–105 were similarlyprepared.

EXAMPLE 85 Preparation ofN-(3-bromophenyl)-7-[2-(1-pyrrolidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

Step 1. Preparation of Example 85:2-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethanol(102)

To a solution of THF (45 mL) was added 0.70 g (1.57 mmol, 1 equiv) ofethyl{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}acetate.A 1M solution of diisobutylaluminum hydride in hexanes (6.43 mL, 6.43mmol, 4.1 equiv) was added to the solution and the reaction was stirredat rt for 1 h. The reaction mixture was quenched with Rochelle's saltfollowed by EtOAc. The solution was separated and the aqueous layerdiscarded and the organic layer was washed with brine (1×25 mL)

and water (1×25 mL). The resulting crude material was purified by flashchromatography eluting with 95:5 CH₂Cl₂/MeOH yielding 630 mg (99%) of102 as a white solid. ¹H-NMR (CDCl₃-d) δ 8.52 (s, 1H), 7.95 (m, 1H),7.56 (m, 1H), 7.24 (m, 2H), 7.11 (s, 1H), 3.84 (m, 2H), 3.08 (m, 3H),2.57 (m, 1H), 2.16 (m, 2H), 1.73 (m, 4H); TLC R_(f)=0.22 (95:5CH₂Cl₂/MeOH); LCMS RT=2.91 min; [M+H]⁺=404.2.

Using the method described above and the appropriate starting materials,Example 64 was similarly prepared.

Step 2. Preparation of Example 85:N-[7-(2-bromoethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]-N-(3-bromophenyl)amine

To a solution of THF (20 mL) was added 0.63 (102, 1.56 mmol, 1 equiv) of2-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}ethanol,0.82 g (3.12 mmol, 2 equiv) triphenylphosphine and 1.03 g (3.12 mmol, 2equiv) carbon tetrabromide. The solution was stirred at rt for 1 h untilcompletion and the reaction mixture was evaporated under reducedpressure. The resulting crude material was purified by flashchromatography eluting with 9:1 CH₂Cl₂/EtOAc yielding 396 mg (54%) of alight yellow solid. ¹H-NMR (CDCl₃-d) δ 8.52 (s, 1H), 7.94 (m, 1H), 7.58(m, 1H), 7.24 (m, 2H), 7.10 (s, 1H), 3.56 (m, 2H), 3.15 (m, 2H), 3.03(m, 1H), 2.57 (m, 1H), 2.19 (m, 2H), 2.04 (m, 2H), 1.68 (m, 1H); TLCR_(f)=0.30 (9:1 CH₂Cl₂/EtOAc); LCMS RT=3.92 min; [M+H]⁺=466.2.

Step 3. Preparation of Example85:N-(3-bromophenyl)-7-[2-(1-pyrrolidinyl)ethyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

To a solution of DMF was added 46 mg (0.10 mmol, 1 equiv) ofN-[7-(2-bromoethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]-N-3-bromophenyl)amine,15 mg (0.10 mmol, 1 equiv) sodium iodide, 21 mg (0.20 mmol, 2 equiv)sodium carbonate, and 14 mg (0.20 mmol, 2 equiv) pyrrolidine. Thesolution was heated at 80° C. for 2 h and upon cooling was purified byprep HPLC (10–90% ACN/H2O). The resulting pure fractions were made basicin aqueous saturated sodium bicarbonate and extracted into EtOAc (10mL). The EtOAc layer was washed with water (1×10 mL) and then collectedand dried over MgSO₄. The solution was evaporated under reduced pressureyielding 24 mg (54%) of desired product 85 as a clear oil. ¹H-NMR(CDCl₃-d) δ 8.52 (s, 1H), 7.94 (m, 1H), 7.58 (m, 1H), 7.22 (m, 2H), 7.13(s, 1H), 3.10 (m, 2H), 3.00 (m, 1H), 2.59 (m, 7H), 2.16 (m, 1H), 1.98(m, 1H), 1.84 (m, 4H), 1.70 (m, 3H); TLC R_(f)=0.23 (9:1 CH₂Cl₂/MeOH);LCMS RT=2.33 min; [M+H]⁺=457.2.

Using the method described above and the appropriate starting materials,Examples 54, 59, 73–76, 78–80, 84–89, 93–94 and 96–100 were similarlyprepared.

EXAMPLE 90 Preparation ofN-(3-bromophenyl)-7-(2-methoxyethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-amine

To a solution of DMF were added 52 mg (0.11 mmol, 1 equiv) ofN-[7-(2-bromoethyl)5,6,7,8tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yl]-N-(3-bromophenyl)amine,17 mg (0.11 mmol, 1 equiv) sodium iodide, and 18 mg (0.33 mmol, 3 equiv)sodium methoxide. The solution was heated at 80° C. for 2 h and uponcooling the solution was purified by prep HPLC (10–90% ACN-H₂O). Theresulting pure fractions were made basic in aqueous saturated sodiumbicarbonate and extracted into EtOAc (10 mL). The EtOAc layer was washedwith water (1×10 mL) and dried over MgSO₄. The solution was evaporatedunder reduced pressure yielding 20 mg (44%) of desired product, 90, as awhite solid. ¹H-NMR (CDCl₃-d) δ 8.52 (s, 1H), 7.94 (m, 1H), 7.59 (m,1H), 7.24 (m, 2H), 7.13 (s, 1H), 3.55 (t, 2H), 3.39 (s, 3H), 3.12 (m,2H), 3.01 (m, 1H), 2.56 (m, 1H), 2.13 (m, 2H), 1.74 (m, 3H); TLCR_(f)=0.75 (9:1 CH₂Cl₂/MeOH); LCMS RT=3.57 min; [M+H]⁺=418.2.

Using the method described above and the appropriate starting materials,Example 101 was similarly prepared.

EXAMPLE 95 Preparation of1-{4-[(3-bromophenyl)amino]-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-7-yl}-2-methyl-2-propanol

The compound was prepared as described in Example 27 with the exceptionthat imidazole was used in place of piperidine.

¹H-NMR (CD₂Cl₂-d₄) δ 8.35 (s, 1H), 7.94 (s, 1H), 7.49–7.46 (m, 1H),7.14–7.12 (m, 2H), 7.10 (s, 1H), 3.03–2.97 (m, 3H), 2.55–2.45 (m, 1H),2.12–2.02 (m, 2H), 1.56–1.46 (m, 4H), 1.99 (s, 6H); LCMS RT=3.32 min;[M+H]⁺=432.3.

EXAMPLE 136 Preparation of{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-aceticacid ethyl ester

Step 1. Preparation of 3-Chloro-4-(3-fluoro-benzyloxy)phenylamine

2-Chloro-1-(3-fluoro-benzoyloxy)-4-nitro-benzene 10 g (35.5 mmol, 1 eq)was suspended in 50 mL acetic acid and 150 mL ethyl acetate in a 500 mLflask. Iron 9.9 g (177.5 mmol, 5 eq) was added to this suspension. Thereaction was stirred at rt overnight. The reaction mixture was filteredthrough celite pad. The filtrate was concentrated in vacuo andneutralized with sat. Na₂CO₃ solution, followed by ethyl acetateextraction. The organic layer was washed with brine and concentrated invacuo. The resulting crude material was purified by flash chromatographyeluting with 15% ethyl acetate/hexane yielding 8.5 g of3-chloro-4-(3-fluoro-benzyloxy)-phenylamine as a brown solid (95%, TLCRf=0.4, 30% AcOEt/HEX.).

¹H-NMR (CDCl₃) δ 3.5 (s, 2H), 5.0 (s, 2H), 6.5 (dd, 1H), 6.76 (m, 2H),7.0 (m, 1H), 7.2 (m,2H), 7.32 (m,1H).

Following the same procedure 3-Chloro-4-(4-fluoro-benzyloxy)-phenylaminewas prepared as well (TLC Rf=0.4, 30% AcOEt/HEX.). ¹H-NMR (CDCl3) δ 3.5(s, 2H), 5.0 (s, 2H), 6.5 (dd, 1H), 6.76 (m, 2H), 7.05 (m, 2H), 7.4 (m,2H).

Step 2. Preparation of Example 136:{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-aceticacid ethyl ester

The compound was prepared as described in Example 14, Step 4.

¹H-NMR (CDCl₃) δ 1.2 (t, 3H), 1.7 (1H), 2.15 (1H), 2.45 (3H), 2.6 (1H),3.1 (3H), 4.1 (q, 2H), 5.14 (s, 2H), 6.9 (2H), 7.0 (td, 1H), 7.2 (2H),7.33 (m, 1H), 7.42 (dd, 1H), 7.69 (d, 1H), 8.45 (s, 1H). LCMS RT=4.01min; [M+H]⁺=526.2.

EXAMPLE 137 Preparation of2-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethanol

To a solution of THF (40 mL) was added 7 g (13.3 mmol, 1 equiv) of{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-aceticacid ethyl ester. A 1M solution of diisobutylaluminum hydride in hexanes(53 mL, 53 mmol, 4 equiv) was added to the solution and the reaction wasstirred at rt for 3 h. The reaction mixture was quenched with Rochelle'ssalt followed by EtOAc. The solution was separated and the aqueous layerdiscarded and the organic layer was washed with brine (100 mL) and water(100 mL). The resulting material 5.5 g (85%)was pure white solid ofExample 137. ¹H-NMR (DMSO-d6) δ 1.5 (m, 3H), 1.95 (m, 2H), 2.93 (dd,1H),3.16 (2H), 3.53 (m,2H), 4.45 (t, 1H), 5.2 (s, 2H), 7.17 (m, 2H), 7.28(m,2H), 7.43 (m, 1H), 7.5 (dd, 2H), 7.76 (dd, 1H), 8.05 (s, 1H). LCMSRT=3.46 min; [M+H]⁺=484.2.

EXAMPLE 138 Preparation of[7-(2-Bromo-ethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine

The compound was prepared as described in Example 85, Step 2.

¹H-NMR (CDCl3) δ 1.68 (1H), 2.02 (m, 2H), 2.18 (2H), 2.54 (1H), 3.0 (dd,1H), 3.1 (2H), 3.55 (m, 2H), 5.15 (s, 2H), 6.94 (2H), 7.02 (m, 1H), 7.21(m, 2H), 7.35 (m, 1H), 7.42 (dd, 1H), 7.71 (d, 1H), 8.46 (s, 1H). LCMSRT=4.41 min; [M+H]⁺=546.3.

EXAMPLE 160 Preparation of[3-chloro-4-(3-fluoro-benzyloxy)-phenyl-{7-[2-(3-dimethylamino-pyrrolidin-1-yl)-ethyl]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl}-amine

The compound was prepared as described in Example 85, Step 3.

¹H-NMR (CDCl3) δ 1.70 (m, 3H), 2.00 (m, 2H), 2.10 (2H), 2.22 (s, 6H),2.30 (m, 1H), 2.50 (m, 4H), 2.80 (m, 2H), 3.00 (m, 4H), 5.12 (s,2H),6.94 (2H), 7.02 (m, 1H), 7.21 (m, 2H), 7.35 (m, 1H), 7.42 (dd, 1H), 7.71(d, 1H), 8.44 (s, 1H). LCMS RT=1.87 min; [M+H]+=580.2

Using the method described above and the appropriate starting materials,Examples 139, 140, 142–172, 186, 197, 200 were similarly prepared.

EXAMPLE 173 Preparation of{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-aceticacid ethyl ester

Step 1. Preparation of Example 173:3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine

2-chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-pycolyl chloridehydrogen chloride 9.45 g (57.6 mmol, 1 eq) cesium carbonate 41.3 (126.8mmol, 2.2 eq) and sodium iodide 8.64 g (57.6 mmol, 1 eq) were suspendedin 200 mL acetonitrile. The reaction mixture was stirred at 60° C. for 5h. The resulted suspension was filtered and washed with 400 mL water,yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52%) as a redsolid.

2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2 mmol, 1 eq) and8.44 g iron (151.1 mmol, 5 eq) were mixed in 100 mL acetic acid and 50mL ethyl acetate and were stirred at rt overnight. The reaction mixturewas filtered through celite pad. The filtrate was concentrated in vacuoand neutralized with sat. Na₂CO₃ solution. The solution was extractedwith ethyl acetate and the organic layer was washed with brine andconcentrated in vacuo. The resulting crude material was purified byflash chromatography eluting with 30% ethyl acetate/hexane yielding 3.2g of 3-chloro-4-(pyridin-2-ylmethoxy)-phenylamine as a white solid(52%). ¹H-NMR (CDCl₃) δ 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H), 6.80(d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMSRT=0.89 min; [M+H]⁺=235.1.

Step 2. Preparation of Example 173:{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-aceticacid ethyl ester

The compound was prepared as described in Example 14, Step 4.

¹H-NMR (CD₃OD) δ 8.78 (s, 1H), 8.39 (s, 1H), 8.36 (t, 1H), 8.03 (d,J=7.9 Hz, 1H), 7.8 (m, 2H), 7.51 (dd, J=2.8, 8.8 Hz, 1H), 7.26 (d, J=8.8Hz, 1H), 5.46 (s, 2H), 4.18 (q, 2H), 3.26–3.05 (m, 3H), 2.65 (m, 1H),2.50 (d, J=7.0 Hz, 2H), 2.42 (m, 1H), 2.16 (m, 1H), 1.70 (m, 1H), 1.29(t, 3H). LCMS RT=3.18 min; [M+H]⁺=509.

EXAMPLE 174 Preparation of2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethanol

The compound was prepared as described in Example 137.

¹H-NMR (CDCl₃) δ 1.75 (m, 3H), 2.12 (2H), 2.58 (m, 1H), 3.02 (m, 3H),3.48 (s, 1H), 3.80 (t, 2H), 5.24 (s, 2H), 6.98 (m, 2H), 7.21 (m, 1H),7.40 (dd, 1H), 7.62 (d, 1H), 7.70 (m, 2H), 8.42 (s, 1H), 8.60 (d, 1H).LCMS RT=3.03 min; [M+H]⁺=467.2.

EXAMPLE 175 Preparation of Methanesulfonic acid2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethylester

Methanesulfonyl chloride (0.48 mL, 707 mg, 6.17 mmol, 1.2 equiv.) wasadded to a suspension of2-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethanol(2.4 g, 5.14 mmol, 1 equiv.) in anhydrous DCM (20 mL) at 0° C. Theresulting mixture was stirred overnight during which time it was warmedto ambient temperature. The standard aqueous work-up gaveMethanesulfonic acid2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethylester as a slight yellow solid (2.3 g, 79%). ¹H-NMR (CD₃OD) δ 8.56 (s,1H), 8.33 (s, 1H), 7.85 (t, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.55 (d, J=7.9Hz, 1H), 7.51 (dd, J=2.5, 9.1 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J=8.8 Hz,1H), 5.27 (s, 2H), 4.35 (t, 2H), 3.19 (s, 3H), 3.15 (m, 3H), 2.97 (m,1H), 2.17 (m, 2H), 1.81 (m, 2H), 1.54 (m, 1H).; LCMS RT=3.03 min;[M+H]⁺=545.

EXAMPLE 177 Preparation of[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-[7-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-amine

Morpholine (0.03 mL, 26. mg, 0.30 mmol, 1.2 equiv.) was added to asuspension of Methanesulfonic acid2-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethylester (135 mg, 0.25 mmol, 1 quiv.) and DIEA (0.09 mL, 0.5 mmol, 2equiv.) in anhydrous acetonitrile (2.0 mL). The resulting mixture wasstirred overnight at 80° C. at which time TLC (MeOH/DCM 5:95) indicatedno more starting material left. The solvents were evaporated and residuewas purified by preparative TLC (20 cm×20 cm×1 mm silica, MeOH/DCM 5:95)to give[3-Chloro-4-(pyridin-2-ylmethoxy)-phenyl]-[7-(2-morpholin-4-yl-ethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-amineas a white solid (16 mg, 12%). ¹H-NMR (CD₃OD) δ 8.51 (s, 1H), 8.24 (s,1H), 7.87 (t, 1H), 7.81 (d, J=2.4 Hz, 1H) 7.68 (d, J=7.5 Hz, 1H), 7.36(m, 2H), 7.02 (d, J=9.2 Hz, 1H), 5.18 (s, 2H), 2.69 (t, 4H), 3.35 (s,1H), 3.11 (m, 1H), 3.02 (m, 1H), 2.91 (m, 1H), 2.48 (m, 6H), 2.09 (m,1H), 1.89 (m, 1H), 1.62 (m, 3H).; LCMS RT=2.25 min; [M+H]⁺=536.

Using the method described above and the appropriate starting materials,Examples 141, 173–185, 187 and 196 were similarly prepared.

EXAMPLE 203 Preparation of2-[4-(1-Benzyl-1H-indazol-5-ylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl]-ethanol

Step 1. Preparation of Example 203: 1-Benzyl-1H-indazol-5-ylamine

To a solution of 5-nitroindazole (10.0 g, 61.3 mmol) in acetonitrile(100 mL) was added potassium carbonate (16.9 g, 122.6 mmol) and benzylbromide (13.6 g, 79.7 mmol). The resulting yellow reaction mixture washeated with stirring at 70° C. overnight. Upon cooling down, the solidwas filtered off and washed with methylene chloride. The filtrate wasconcentrated to dryness and the resulting residue was purified by flashchromatography eluting with 17–25% ethyl acetate in hexanes (v/v)yielding 7.0 g (44%) of the corresponding 1-Benzyl-5-nitro-1H-indazoleas a yellow solid.

7.61 g (136 mmol, 5 equiv) of Iron powder (4.03 g, 72.1 mmol) was addedslowly to the solution of 1-Benzyl-5-nitro-1H-indazole (6.9 g, 27.2mmol) in acetic acid (200 mL). After stirring at room temperatureovernight, the reaction mixture became milky with formation of a whiteprecipitate. The precipitate was filtered off and the filtrate wasconcentrated to ca. 20 mL. The residue was diluted with water (200 mL)and neutralized by slow addition of sodium hydroxide. The mixture wasthen extracted with ethyl acetate (500×5 mL). The organic layer werecombined, dried over sodium sulfate, filtered and concentrated todryness to afford 1-benzyl-1H-indazol-5-ylamine (5.23 g, 82%) as a brownsolid. ¹H NMR (DMSO-d₆): δ 7.72 (s, 1H), 7.35 (d, J=8.8 Hz, 1H),7.24–7.14 (m, 5H), 6.74 (m, 2H), 5.49 (s, 2H), 4.80 (br, 2H). ES-LCMS:RT=0.93 min; [M+H]⁺=224.2.

Step 2. Preparation of Example 203:[4-(1-Benzyl-1H-indazol-5-ylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl]-aceticacid ethyl ester

The compound was prepared as described in Example 14, Step 4.

¹H-NMR (DMSO-d₆) δ 8.76 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.98 (d,J=2.6 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.52 (dd, J=8.9, 2.0 Hz, 1 H),7.24–7.24 (m, 5H), 5.68 (s, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.22 (m, 2H),3.02 (dd, J=17.0. 4.7 Hz, 1H), 2.63–2.45 (m, 3H), 2.28 (m, 1H), 2.01 (d,J=13.7 Hz, 1H), 1.58 (m, 1H), 1.21 (t, J=7.1 Hz, 3H). LCMS RT=3.34 min;[M+H]⁺=498.3.

Step 3. Preparation of Example 203:2-[4-(1-Benzyl-1H-indazol-5-ylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl]-ethanol

To a solution of THF (100 mL) was added 4.50 g (9.04 mmol, 1 equiv) of[4-(1-Benzyl-1H-indazol-5-ylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl]-aceticacid ethyl ester. A 1M solution of diisobutylaluminum hydride in THF(45.2 mL, 45.2 mmol, 5 equiv) was added to the solution at 0° C. and thereaction was stirred for 30 min before warming up to rt and stirring for2 h. The reaction mixture was quenched with Rochelle's salt followed byEtOAc. The solution was separated and the aqueous layer discarded andthe organic layer was washed with brine (200 mL) and water (100 mL). Theresulting crude material was purified by flash chromatography elutingwith 95/5 CH₂Cl₂/MeOH yielding 850 mg (21%) of Example 203 as a whitesolid. ¹H-NMR (CD₂Cl₂) δ 8.36 (s, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.01 (s,1H), 7.46–7.19 (m, 8H), 5.60 (s, 2H), 3.77 (q, J=4.4 Hz, 2H), 3.21–2.96(m, 3H), 2.56 (m, 1H), 2.11 (m, 2H), 1.67 (m, 3H), 1.45 (t, J=4.4 Hz,1H). LCMS RT=2.68 min; [M+H]⁺=456.3.

EXAMPLE 214 Preparation of2-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethanol

Step 1. Preparation of Example 214:3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamine

To a DMF suspension (60 mL) of sodium hydride (1.39 g, 60% in mineraloil) was slowly added a DMF solution (40 mL) of5-hydroxy-2-methylpyridine (3.80 g, 34.8 mmol) dropwise, keeping thetemp <5° C. The ice bath was removed, and the contents allowed to warmwith stirring for 60 min. To the light yellow colored contents was addeda DMF solution of 2-fluoro-5-nitrotoluene (4.50 g, 29.0 mmol) dropwise,and the contents heated to 95° C., overnight. The dark brown contentswere removed from heating, and allowed to cool to rt with stirring. Themixture was quenched with water (5 mL), and concentrated in vacuo. Theresidue was diluted with water (100 mL) and EtOAc (75 mL). The layerswere separated, and the aq. layer extracted with EtOAc (2×75 mL). Thecombined organic layers were washed with brine (2×50 mL), dried overMgSO4, filtered and concentrated in vacuo to collect the2-Methyl-5-(2-methyl-4-nitro-phenoxy)pyridine as a yellow oil (7.0 g,94%).

The solution of 2-Methyl-5-(2-methyl-4-nitro-phenoxy)-pyridine (6.4 g,26.2 mmol), 10 wt % Pd/C (0.50 g) in ethanol (100 mL) was stirred under1 atm hydrogen at rt for 24 h. Then the Pd/C catalyst was removed byfiltration through a layer of celite. Removal of the solvent gave thedesired product as an off-white solid (5.55 g, 99%). ¹H-NMR (DMSO-d6) δ8.04 (d, J=2.7 Hz, 1H), 7.13 (d, J=5.4 Hz, 1H), 7.02 (dd, J=8.7, 3.1 Hz,1H), 6.68 (d, J=8.7 Hz, 1H), 6.49 (d, J=2.6 Hz, 1H), 6.42 (dd, J=8.4,2.8 Hz, 1H), 4.96 (br, 2H), 2.39 (s, 3H), 1.97 (s, 3H). LCMS RT=1.04min; [M+H]⁺=215.2.

Step 2. Preparation of Example 214:{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-aceticacid ethyl ester

The compound was prepared as described in Example 14, Step 4.

¹H-NMR (CDCl₃) δ 8.49 (s, 1H), 8.26 (d, J=1.7 Hz, 1 H), 7.52 (s, 1H),7.47 (dd, J=8.5, 2.6 Hz, 1H), 7.16–7.05 (m, 3H), 6.91 (d, J 8.5 Hz, 1H),4.18 (q, J=7.2 Hz, 2H), 3.14–3.04 (m, 3H), 2.60 (m, 1H), 2.53 (d, J=2.0Hz, 3H), 2.46 (s, 3H), 2.27 (s, 3H), 2.17 (m, 1H), 1.71 (m, 1H), 1.30(q, J=7.2 Hz, 3H). LCMS RT=2.52 min; [M+H]⁺=489.4.

Step 3. Preparation of Example 214:2-{4-[3-Methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethanol

The compound was prepared as described in Example 203, Step 3.

¹H-NMR (CD₂Cl₂) δ 8.40 (s, 1H), 8.20 (dd, J=2.6, 1.0 Hz, 1H), 7.52 (m,2H), 7.11 (m, 3H), 6.91 (d, J=8.5 Hz, 1H), 3.76 (q, J=4.2 Hz, 2H),3.17–2.94 (m, 3H), 2.55 (m, 1H), 2.48 (s, 3H), 2.25 (s, 3H), 2.11 (m,2H), 1.98 (t, J=4.2 Hz, 1H), 1.88–1.74 (m, 1H). LCMS RT=2.21 min;[M+H]⁺=447.2.

EXAMPLE 235 Preparation of{7-[2-(2,5-Dimethyl-pyrrolidin-1-yl)-ethyl]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl}-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamine

Step 1. Preparation of Example 235: Methanesulfonic acid2-{4-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-ethylester

To the suspension of Example 214 (2.18 g 4.9 mmol) in acetonitrile (55mL) containing pyridine (1.27 g, 16.1 mmol) at 0° C. was added methylsulfonic anhydride (1.53 g, 8.8 mmol) in several portions. Then thereaction mixture was stirred at rt overnight until no Example 214 wasleft. The reaction mixture was poured into ethyl acetate/brine (400mL/150 mL). The organic layer after extraction was washed with saturatedsodium carbonate, water in sequence, dried over sodium sulfate,concentrated to get the product (2.44 g, 90%) as a yellow foamy solid.¹H-NMR (CD₂Cl₂) δ 8.41 (s, 1H), 8.20 (s, 1H), 7.52 (m, 2H), 7.10 (m,3H), 6.89 (d, J=8.5, 1H), 4.37 (t, J=6.4 Hz, 2H), 3.20–2.98 (m, 3H),3.02 (s, 3H), 2.59 (m, 1H), 2.48 (s, 3H), 2.26 (s, 3H), 2.15 (br, 2H),1.90 (m, 2H), 1.68 (m, 1H). LCMS RT=2.90 min; [M+H]⁺=525.2.

Step 2. Preparation of{7-[2-(2,5-Dimethyl-pyrrolidin-1-yl)-ethyl]-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl}-[3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-amine

The compound was prepared as described in Example 177. ¹H-NMR (CD₂Cl₂) δ8.40 (s, 1H), 8.19 (d, J=2.4, 0.9 Hz, 1H), 7.54–7.50 (m, 2H), 7.12–7.08(m, 3H), 6.90 (d, J=8.5 Hz, 1H), 3.16–2.92 (m, 4H), 2.76–2.54 (m, 4H),2.47 (s, 3H), 2.24 (s, 3H), 2.12 (br, 1H), 1.95 (m, 2H), 1.79 (m, 1H),1.66–1.53 (m, 3H), 1.37–1.32 (m, 2H), 1.06 (d, J=6.1 Hz, 3H), 0.95 (d,J=6.3 Hz, 3H). LCMS RT=1.97 min; [M+H]⁺=528.3.

Using the method described above and the appropriate starting materials,Examples 213–227, 230–234, and 236 were similarly prepared.

EXAMPLE 239 Preparation of(1-Benzyl-1H-indazol-5-yl)-[7-(2-piperidine-1-yl-ethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-amine

Step 1. Preparation of Example 239: Methanesulfonic acid2-[4-(1-benzyl-1H-indazol-5-ylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl]-ethylester

The compound was prepared as described in Example 235, Step 1.

¹H-NMR (CD₂Cl₂) δ 8.37 (s, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.02 (d, J=1.0Hz, 1H), 7.47–7.16 (m, 8H), 5.60 (s, 2H), 4.37 (t, J=6.4 Hz, 2H),3.18–2.98 (m, 3H), 3.02 (s, 3H), 2.58 (m, 1H), 2.15 (br, 2H), 1.90 (m,2H), 1.68 (m, 1H). LCMS RT=3.02 min; [M+H]⁺=534.2.

Step 2. Preparation of(1-Benzyl-1H-indazol-5-yl)[7-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-4-yl]-amine

The compound was prepared as described in Example 177. ¹H-NMR (CD₂Cl₂) δ8.35 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 8.00 (s, 1H), 7.42–7.27 (m, 5H),7.21 (d, J=1.8 Hz, 1H), 7.16 (d, J=4.7 Hz, 2H), 5.58 (s, 2H), 3.18–2.90(m, 3H), 2.56–2.47 (m, 1H), 2.44–2.33 (m, 5H), 2.08–1.95 (m, 3H),1.64–1.50 (m, 7H), 1.41 (m, 2H). LCMS RT=2.47 min; [M+H]⁺=523.4.

Using the method described above and the appropriate starting materials,Examples 202–212, 227–229, and 237–238 were similarly prepared.

EXAMPLE 242 Preparation ofN4-(3-chloro-4-fluorophenyl)-N7-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4,7-diamine

Step 1. Preparation of Ethyl2-amino-4,7-dihydro-5H-spiro[1-benzothiophene-6,2′-[1,3]dioxolane]-3-carboxylate

To 600 mL ethanol were sequentially 1,4-Dioxa-spiro[4,5]decan-8-one(25.0 g, 0.160 mol), ethyl cyanoacetate (18.1 g, 0.160 mol), morpholine(14.0 g, 0.160 mol), and sulfur (5.5 g, 0.160 mol). The heterogeneouscontents were stirred at room temperature for 4 days, after which timeall the sulfur had dissolved. The homogenous contents were concentratedunder reduced pressure, and the residue diluted with ethyl acetate (200mL). The mixture was washed with water (200 mL), and the layersseparated. The organic layer was dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford the desired product as adark colored oil (45.0 g, 99%). ¹H-NMR (DMSO-d₆) δ 7.20 (s, 2H), 4.10(q, 2H), 3.87 (s, 4H), 2.66 (t, 2H), 2.59 (s, 2H), 1.71 (t, 2H), 1.18(t, 3H); LCMS RT=2.58 min; [M+H]⁺=284.2.

Step 2. Preparation of3,5,6,8-tetrahydro-4H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-one

To a stirring 225 mL formamide solution of ethyl2-amino-4,7-dihydro-5H-spiro[1-benzothiophene-6,2′-[1,3]dioxolane]-3-carboxylate(40.0 g, 0.142 mol) was added ammonium formate (17.8 g, 0.282 mol). Thecontents were stirred with heating at 140° C. for 16 h, after which timethe heterogeneous contents were removed from heating, and allowed tocool to rt. The contents were filtered, the solid filter cake washedwith water (2×60 mL), and suction dried overnight to afford the desiredproduct as an off-white solid (33.0 g, 88%). ¹H-NMR (DMSO-d₆) δ 12.35(broad s, 1H), 8.00 (s, 1H), 3.92 (s, 4H), 2.95 (t, 2H), 2.91 (s, 2H),1.83 (t, 2H); LCMS RT=1.87 min; [M+H]⁺=265.2.

Step 3. Preparation of4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane]

To a stirring 0° C. POCl₃ (200 mL) solution of3,5,6,8-tetrahydro-4H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-one(20.0 g, 0.076 mol) was added triethylamine (200 mL) from a droppingfunnel over a 15 min. period. The contents were allowed to warm to rt,and then heated to 80° C. After 3 h, the contents were removed fromheating, and allowed to cool to rt. The heterogeneous mixture wasconcentrated under reduced pressure, the residue diluted with ethylacetate (100 mL), and again concentrated. The residue was diluted withethyl acetate (100 mL) and the heterogeneous mixture poured onto astirring mixture of ice-water/sq. NaHCO₃ (800 mL). After 5 min.stirring, the now pH=7 contents were filtered and the solid filter cakewashed with water. The product was dried in vacuum oven overnight toafford the desired product (20.7 g, 97%) as an off-white solid. ¹H-NMR(DMSO-d₆) δ 8.82 (s, 1H), 3.97 (s, 4H), 3.10 (t, 2H), 3.07 (s, 2H), 1.95(t, 2H); LCMS RT=2.45 min; [M+H]⁺=283.1.

Step 4. Preparation ofN-(3chloro-4-fluorophenyl)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine:

To a stirring ethanol solution (100 mL) of4-chloro-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolane](7.0 g, 24.8 mmol) was added 4-fluoro-3-chloroaniline (3.6 g, 24.8 mmol)and 0.05 mL 4N HCl (in dioxane). The contents were heated to reflux for5 h, after which time the contents were removed from heating and allowedto cool to rt. The solvent was removed under reduced pressure, the cruderesidue suspended in aq. NaHCO₃ (100 mL), and stirred for 15 min. Thecontents were again filtered, and the solid filter cake washed withwater. The collected yellow solid was triturated with diethyl ether (50mL) to afford the final product (5.5 g, 57%) as a light yellow solid.¹H-NMR (DMSO-d₆) δ 8.41 (s, 1H), 8.28 (s, 1H), 7.78 (dd, 1H), 7.58 (m,1H), 7.35 (t, 1H), 3.97 (s, 4H), 3.22 (t, 2H), 3.00 (s, 2H), 1.93 (t,2H); LCMS RT=3.26 min; [M+H]⁺=392.3.

Step 5. Preparation of4-(3Chloro-4-fluoro-phenylamino)-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one

To a stirring acetic acid/water solution (4:1, 300 mL) was addedN-(3-chloro-4-fluorophenyl)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine(5.5 g, 14 mmol), and the contents heated at 80° C. for 12 h. The darkcolored mixture was cooled to rt, and the solvent removed under reducedpressure. The crude residue was suspended in 1N NaHCO₃ (100 mL), stirredfor 10 min., and filtered. The filtered solid was triturated withdiethyl ether (100 mL) to afford the desired product (4.8 g, 98%) as adark yellow solid. ¹H-NMR (DMSO-d₆) δ 8.53 (s, 1H), 8.46 (s, 1H), 7.87(dd, 1H), 7.60 (m, 1H), 7.40 (t, 1H), 3.73 (s, 2H), 3.43 (t, 2H), 2.64(s, 2H); LCMS RT=3.01 min; [M+H]⁺=348.2.

Step 6. Preparation ofN4-(3-chloro-4-fluorophenyl)-N7-(2-morpholin-4-ylethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4,7-diamine

To a stirring DCE/THF solution (1:1, 16 mL) of4-(3-chloro-4-fluoro-phenylamino)-5,8-dihydro-6H-benzo[4,5]thieno[2,3-d]pyrimidin-7-one(150 mg, 0.43 mmol) was added 1-N-(2-aminoethyl)morphine (62 mg, 0.47mmol), sodium triacetoxyborohydride (137 mg, 0.65 mmol), and 2 drops ofacetic acid. The contents were stirred at rt for 3 h, after which timethe stirring was halted and the solvent removed under reduced pressure.The residue was diluted with ethyl acetate (5 mL) and washed with water(5 mL). The organic layer was separated, dried over Na₂SO₄, filtered,and concentrated under reduced pressure. The crude product was purifiedby reverse phase HPLC to afford the desired product (30 mg, 15%). ¹H-NMR(DMSO-d₆) δ 8.40 (s, 1H), 7.82 (dd, 1H), 7.50 (m, 1H), 7.23 (t, 1H),3.94 (t, 4H), 3.80 (m, 1H), 3.66 (t, 2H), 3.49 (t, 2H), 3.37 (m, 1H),3.29–3.35 (m, 6H), 3.06 (m, 1H), 2.48 (m, 1H), 2.07 (m, 1H); LCMSRT=1.89 min; [M+H]⁺=462.1.

Using the method described above and the appropriate starting materials,Examples 240–243 were similarly prepared.

Compositions Useful for the Method of this Invention

A compound of Formula I is useful in this method for treating theconditions described further herein when it is formulated as apharmaceutically acceptable composition. A pharmaceutically acceptablecomposition is a compound of Formula I in admixture with apharmaceutically acceptable carrier. A pharmaceutically acceptablecarrier is any carrier that is relatively non-toxic and innocuous to apatient at concentrations consistent with effective activity of theactive ingredient so that any side effects ascribable to the carrier donot vitiate the beneficial effects of the active ingredient.

Commonly used pharmaceutical ingredients which can be used asappropriate to formulate the composition for its intended route ofadministration include:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃);

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate);

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection);

chelating agents (examples include but are not limited to edetatedisodium and edetic acid);

colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate);

flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas);

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures);

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

The compounds of the present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms formulated as immediate, slowor timed release preparations, including, for example, the following.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule which can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in a physiologically acceptable diluent with a pharmaceuticalcarrier which can be a sterile liquid or mixture of liquids such aswater, saline, aqueous dextrose and related sugar solutions, an alcoholsuch as ethanol, isopropanol, or hexadecyl alcohol, glycols such aspropylene glycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acidglyceride, or an acetylated fatty acid glyceride, with or without theaddition of a pharmaceutically acceptable surfactant such as a soap or adetergent, suspending agent such as pectin, carbomers, methycellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulation ranges from about 5% to about15% by weight. The surfactant can be a single component having the aboveHLB or can be a mixture of two or more components having the desiredHLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such material are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations whichare known in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238–311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53(6), 324–349; andNema, S. et al, “Excipients and Their Use in Injectable Products” PDAJournal of Pharmaceutical Science & Technology 1997, 51(4), 166–171.

It is believed that one skilled in the art, utilizing the precedinginformation, can utilize the present invention to its fullest extent.Nevertheless, the following are examples of pharmaceutical formulationsthat can be used in the method of the present invention. They are forillustrative purposes only, and are not to be construed as limiting theinvention in any way.

Pharmaceutical compositions according to the present invention can befurther illustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention is made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1–2mg/mL with sterile 5% dextrose and is administered as an IV infusionover 60 min.

Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100–1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32–327 mg/mL sodium citrate, and (iii)300–3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2–0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15–60 min.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

-   -   50 mg/mL of the desired, water-insoluble compound of this        invention    -   5 mg/mL sodium carboxymethylcellulose    -   4 mg/mL TWEEN 80    -   9 mg/mL sodium chloride    -   9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit was 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Cancer

The compounds and compositions described herein can be used to treat orprevent hyper-proliferative disorders. An effective amount of a compoundor composition of this invention can be administered to a patient inneed thereof in order to achieve a desired pharmacological effect. Apatient, for the purpose of this invention, is a mammal, including ahuman, in need of treatment (including prophylactic treatment) for aparticular disorder described further herein. A pharmaceuticallyeffective amount of compound or composition is that amount whichproduces a desired result or exerts an influence on the particularhyper-proliferative disorder being treated.

Hyper-proliferative disorders include but are not limited to solidtumors, such as cancers of the breast, respiratory tract, brain,reproductive organs, digestive tract, urinary tract, eye, liver, skin,head and neck, thyroid, parathyroid and their distant metastases. Thosedisorders also include lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgkin's disease,and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

The disorders described above have been well characterized in humans,but also exist with a similar etiology in other mammals. Accordingly,the method of this invention can be administered to mammals, includinghumans, in need thereof for the treatment of angiogenesis and/orproliferative dependent disorders.

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.Stem Cells 1993, 11(6), 528–35), taxotere (Bissery et al. Anti CancerDrugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al.Cancer Chemother. Pharmacol. 1996, 37(5), 385–93) were demonstrated withthe use of in vitro tumor proliferation assays.

The compounds and compositions described herein, including salts andesters thereof, exhibit anti-proliferative activity and are thus usefulto prevent or treat the disorders associated with hyper-proliferation.The following assay is one of the methods by which compound activityrelating to treatment of the disorders identified herein can bedetermined.

In vitro Tumor Cell Proliferation Assay

The tumor cell proliferation assay used to test the compounds of thepresent invention involves a readout called Cell Titer-Glow® LuminescentCell Viability Assay developed by Promega (Cunningham, B A “A GrowingIssue: Cell Proliferation Assays, Modern kits ease quantification ofcell growth” The Scientist 2001, 15(13), 26, and Crouch, S P et al.,“The use of ATP bioluminescence as a measure of cell proliferation andcytotoxicity” Journal of Immunological Methods 1993, 160, 81–88), thatmeasures inhibition of cell proliferation. Generation of a luminescentsignal corresponds to the amount of ATP present, which is directlyproportional to the number of metabolically active (proliferating)cells.

A431cells (human epidermoid carcinoma, ATCC # HTB-20) and BT474 (humanbreast carcinoma, ATCC # CRL-1555) were plated at a density of 2.5×10³cells/well in 96 well black-clear bottom tissue culture plates in RPMImedia with 10% Fetal Bovine Serum and incubated at 37° C. Twenty-fourhours later, test compounds are added at a final concentration rangefrom as high 100 μM to as low 64 pM depend on the activities of thetested compounds in serial dilutions at a final DMSO concentration of0.1%. Cells were incubated for 72 hours at 37° C. in complete growthmedia after addition of the test compound. After 72 hours of drugexposure, the plates were equilibrated to room temperature forapproximately 30 min. Then, using a Promega Cell Titer Glo Luminescent®assay kit, lysis buffer containing 100 microliters of the enzymeluciferase and its substrate, luciferin mixture, was added to each well.The plates were mixed for 2 min on orbital shaker to ensure cell lysisand incubated for 10 min at room temperature to stabilize luminescencesignal. The samples were read on VICTOR 2 using Luminescence protocol,and analyzed with Analyze5 software to generate IC50 values.Representative compounds of this invention showed inhibition of tumorcell proliferation in this assay.

For determination of IC50's, a linear regression analysis can be used todetermine drug concentration which results in a 50% inhibition of cellproliferation using this assay format. The anti-proliferative activitiesof selective sets of compounds are listed below. In A431 cells, Examples4, 15, 22, 26, 45, 54–55, 58–62, 66, 70, 72–75, 77–80, 82–88, 92–94,96–98, 105, 139–142, 145, 148, 150, 152–154, 152–165, 167–171, 175–179,183–186, 189–198, 200, 202–203, 205–212, 221–224, and 230 have IC50'sbelow 5 μM; whereas Examples 1–3, 8, 12, 16, 20, 23, 24, 31, 32, 39, 40,42, 46, 48, 49, 52, 56, 57, 63–65, 67–69, 71, 76, 81, 89, 90, 91, 95,99–103, 136–138, 143–146, 147, 149, 151, 155, 156, 166, 172–174,180–182, 187, 188, 199, 201, 204, 213–220, 225–229, 231–239 have IC50'sbelow 50 μM. In BT474 cells, Examples 2, 4, 15, 22, 36, 39, 42, 43, 45,45, 48, 54, 58–60, 62, 66, 67, 73–75, 77–80, 82, 84, 85–88, 92–99, 101,103, 105, 136–143, 148, 150, 152–200, 202–212, 214–239 have IC50's below5 μM; whereas Examples 1, 3, 8, 12, 16, 20, 23, 24, 31, 32, 40, 49, 52,55–57, 61, 63–65, 68–72, 76, 81, 83, 89–91, 100, 102, 144, 146, 147,149, 151, 201, 213 have IC₅₀'s below 50 μM.

Based upon the above and other standard laboratory techniques known toevaluate compounds useful for the prevention and/or treatment of thediseases or disorders described above by standard toxicity tests and bystandard pharmacological assays for the determination of the preventionand/or treatment of the conditions identified above in mammals, and bycomparison of these results with the results of known medicaments thatare used to treat these conditions, the effective dosage of thecompounds of this invention can readily be determined for preventionand/or treatment of each desired indication. The amount of the activeingredient to be administered in the prevention and/or treatment of oneof these conditions can vary widely according to such considerations asthe particular compound and dosage unit employed, the mode ofadministration, the duration of treatment (including prophylactictreatment), the age and sex of the patient treated, and the nature andextent of the condition to be prevented and/or treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 300 mg/kg, andpreferably from about 0.10 mg/kg to about 150 mg/kg body weight per day.A unit dosage may contain from about 0.5 mg to about 1500 mg of activeingredient, and can be administered one or more times per day. The dailydosage for administration by injection, including intravenous,intramuscular, subcutaneous and parenteral injections, and use ofinfusion techniques will preferably be from 0.01 to 200 mg/kg of totalbody weight. The daily rectal dosage regimen will preferably be from0.01 to 200 mg/kg of total body weight. The daily vaginal dosage regimenwill preferably be from 0.01 to 200 mg/kg of total body weight. Thedaily topical dosage regimen will preferably be from 0.1 to 200 mgadministered between one to four times daily. The transdermalconcentration will preferably be that required to maintain a daily doseof from 0.01 to 200 mg/kg. The daily inhalation dosage regimen willpreferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof administration and number of doses of a compound or composition ofthe present invention or a pharmaceutically acceptable salt or esterthereof can be ascertained by those skilled in the art usingconventional prevention and/or treatment tests.

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with other anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof.

For example, optional anti-hyper-proliferative agents which can be addedto the composition include but are not limited to compounds listed onthe cancer chemotherapy drug regimens in the 11^(th) Edition of theMerck Index, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment and/or prevention ofneoplastic diseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225–1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemonophosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethylmelamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of this invention include but are not limited to otheranti-cancer agents such as epothilone, irinotecan, raloxifen andtopotecan.

It is believed that one skilled in the art, using the precedinginformation and information available in the art, can utilize thepresent invention to its fullest extent. It should be apparent to one ofordinary skill in the art that changes and modifications can be made tothis invention without departing from the spirit or scope of theinvention as it is set forth herein.

1. A compound of formula

wherein R is in each instance selected independently from H,(C₂–C₆)alkenyl, C(O)R⁶, hydroxy, NR⁸⁻¹R⁸⁻¹, and

 or R is (C₁–C₆)alkyl said alkyl being optionally mono-substituted withR⁷, with the proviso that when one R is H, the other R must be otherthan H or methyl, and with the further proviso that when one R ishydroxy, the other R must be other than hydroxy; R¹ is selected from H,OH, halo, CN, NH₂, CF₃, OCF₃, (C₁–C₃)alkyl, (C₂–C₃)alkynyl, and(C₁–C₃)alkoxy; R² is selected from H, OH, halo, NH₂, CN, CF₃, OCF₃,(C₁–C₃)alkyl, (C₂–C₆)alkynyl, (C₁–C₃)alkoxy, (C₁–C₃)alkoxy-phenyl wheresaid phenyl is optionally substituted with 1, 2 or 3 substituents eachselected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN,and OH, and (C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, O-phenyl optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH; O-pyridyl optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH; R³ is selected fromH, OH, halo, NH₂, CN, CF₃, OCF₃, (C₁–C₃)alkyl, (C₂–C₆)alkynyl,(C₁–C₃)alkoxy, (C₁–C₃)alkoxy-phenyl where said phenyl is optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH,(C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionally substituted with1, 2 or 3 substituents each selected independently from (C₁–C₃)alkyl,(C₁–C₃)alkoxy, halo, CF₃, CN, and OH, O-phenyl optionally substitutedwith 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, O-pyridyl optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH;  or R² and R³together with the carbon atoms to which they are attached form apyrazole, where said pyrazole is optionally substituted with 1 or 2substituents each selected independently from methyl, ethyl and benzylor pyridylmethyl, wherein benzyl and pyridylmethyl can optionally besubstituted with 1 or 2 substituents each selected independently frommethyl, halo, cyano and methoxy; R⁴ is selected from H, OH, halo, CN,CF₃, OCF₃, NH₂, (C₁–C₃)alkyl, (C₂–C₆)alkynyl, (C₁–C₃)alkoxy,trifluoromethyl, trifluoromethoxy, (C₁–C₃)alkoxy-phenyl where saidphenyl is optionally substituted with 1, 2 or 3 substituents eachselected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN,and OH, and (C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, O-phenyl optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH; O-pyridyl optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH;  or R⁵ is selectedfrom H, OH, halo, CN, CF₃, OCF₃, NH₂, (C₁–C₃)alkyl, (C₂–C₃)alkynyl, and(C₁–C₃)alkoxy; R⁶ is selected from OH, (C₁–C₆)alkyl, (C₁–C₃)alkoxy,phenyl, pyridyl, NR⁸R⁸,

 NH(C₂–C₆)alkenyl, and a five membered heterocycle optionallysubstituted with a substituent selected from OH, N[(C₁–C₃)alkyl]₂, and(C₁–C₃)alkyl, said alkyl being optionally substituted with a substituentselected from OH, (C₁–C₃)alkoxy, and

R⁷ is selected from OH, halo, (C₁–C₄)alkoxy, phenoxy optionallysubstituted with halo or amino, C(O)R⁶, halo, NR⁸R⁸, imidazolyl, phenyl,indazolyl, aminoindazolyl, —OS(O)₂(C₁–C₃),

 NHC(O)NR⁸R⁸, NHS(O)₂R⁹, NHC(O)-pyrrolidinyl, NHC(O)-morpholinyl, andpyrrolidinyl optionally substituted with one or two substituentsselected from hydroxy, (C₁–C₃)alkoxy, N[(C₁–C₃)alkyl]₂, and (C₁–C₃)alkyloptionally mono -substituted with hydroxy or (C₁–C₃)alkoxy; R⁸ is ineach instance selected independently from H, pyridyl, (C₁–C₄)alkyloptionally mono-substituted with hydroxy, (C₁–C₃)alkoxy,—S(O)₂(C₁–C₃)alkyl, NR¹⁰R¹⁰, or

 and phenyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from CN, OH, halo, CF₃, NR¹⁰R¹⁰ and(C₁–C₃)alkoxy, or

 wherein n is a number from 1 to 5 and R¹⁰ is selected from H and(C₁–C₃)alkyl; R⁸⁻¹ is in each instance selected independently from H,and (C₁–C₄)alkyl optionally mono-substituted with (C₁–C₃)alkoxy,NR¹⁰R¹⁰, or

R⁹ is selected from (C₁–C₃)alkyl, pyridyl, thienyl, and phenyl wheresaid phenyl is optionally substituted with 1, 2, or 3 substituents eachindependently selected from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, CN, OH, halo,CF₃, and NR⁸R⁸; R¹⁰ is selected from H and (C₁–C₃)alkyl; Z is selectedfrom CH₂, O, S, SO, SO₂, and NH, and when Z is NH, H is optionallyreplaced with pyridyl, (C₁–C₃)alkyl optionally substituted with asubstituent selected from hydroxy, (C₁–C₃)alkoxy and pyridyl, or phenyloptionally substituted with 1, 2, or 3 substituents each independentlyselected from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, CN, halo, CF₃, and NR⁸R⁸; Z¹is selected from CH₂, O, S, SO, SO₂, and NH, and when Z¹ is NH, H isoptionally replaced with pyridyl, (C₁–C₃)alkyl optionally substitutedwith a substituent selected from hydroxy, (C₁–C₃)alkoxy and pyridyl, orphenyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, CN, halo, CF₃,and NR⁸R⁸; or a pharmaceutically acceptable salt or ester thereof,excluding the following compounds:5,6,7,8-tetrahydro-7-methyl-N-[4-(phenylmethoxy)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine,monohydrochloride;5,6,7,8-tetrahydro-N-(4-methoxyphenyl)-7-methyl-[1]benzothieno[2,3-]pyrimidin-4-amine,monohydrochloride;5,6,7,8-tetrahydro-7-methyl-N-[3-(trifluoromethyl)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine;N-(3,4-dimethylphenyl)-5,6,7,8-tetrahydro-7-methyl[1]benzothieno-[2,3-d]pyrimidin-4-amine.
 2. The compound of claim 1,wherein R is selected independently from hydrogen and C(O)R⁶, or R is(C₁–C₆)alkyl said alkyl being optionally mono-substituted with R⁷; withthe proviso that when one R is H, the other R must be other than H ormethyl; R¹ is selected from H, OH, halo, CN, NH₂, CF₃, methyl, ethyl,ethynyl, methoxy, and ethoxy; R² is selected from H, OH, halo, NH₂, CN,CF₃, (C₁–C₃)alkyl, (C₂–C₆)alkynyl, (C₁–C₃)alkoxy, (C₁–C₃)alkoxy-phenylwhere said phenyl is optionally substituted with 1, 2 or 3 substituentseach selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃,CN, and OH, and (C₁–C₃)alkoxy-pyridyl, where said pyridyl is optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH, O-phenyl optionallysubstituted with 1, 2 or 3 substituents each selected independently from(C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN, and OH; R³ is selected fromH, OH, halo, NH₂, CN, CF₃, (C₁–C₃)alkyl, (C₂–C₆)alkynyl, (C₁–C₃)alkoxy,(C₁–C₃)alkoxy-phenyl where said phenyl is optionally substituted with 1,2 or 3 substituents each selected independently from (C₁–C₃)alkyl,(C₁–C₃)alkoxy, halo, CF₃, CN, and OH, (C₁–C₃)alkoxy-pyridyl, where saidpyridyl is optionally substituted with 1, 2 or 3 substituents eachselected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN,and OH, O-phenyl optionally substituted with 1, 2 or 3 substituents eachselected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃, CN,and OH, O-pyridyl optionally substituted with 1, 2 or 3 substituentseach selected independently from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, halo, CF₃,CN, and OH; or R²and R³ together with the carbon atoms to which they areattached form a pyrazole, where said pyrazole is optionallyN-substituted with 1 substituent selected from methyl, ethyl and benzyl;R⁴ is H; R⁵ is H; R⁵ is selected from NR⁸R⁸,

 NH(C₂–C₆)alkenyl, and a five membered heterocycle optionallysubstituted with a substituent selected from OH, N[(C₁–C₃)alkyl]₂, and(C₁–C₃)alkyl, said alkyl being optionally substituted with a substituentselected from OH, (C₁–C₃)alkoxy, and

R⁷ is selected from phenoxy optionally substituted with halo or amino,NR⁸R⁸, imidazolyl, indazolyl, aminoindazolyl,

 NHC(O)NR⁸R⁸, NHS(O)₂R⁹, NHC(O)-pyrrolidinyl, NHC(O)-morpholinyl, andpyrrolidinyl optionally substituted with one substituent selected from(C₁–C₃)alkoxy, N[(C₁–C₃)alkyl]₂, and (C₁–C₃)alkyl optionallymono-substituted with (C₁–C₃)alkoxy; R⁸ is in each instance selectedindependently from H, pyridyl, (C₁–C₄)alkyl optionally mono-substitutedwith (C₁–C₃)alkoxy, —S(O(C₁–C₃)alkyl, NR¹⁰R¹⁰, or

 and phenyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from CN, OH, halo, CF₃, NR¹⁰R¹⁰ and(C₁–C₃)alkoxy; R⁹ is selected from (C₁–C₃)alkyl, pyridyl, thienyl, andphenyl where said phenyl is optionally substituted with 1, 2, or 3substituents each independently selected from (C₁–C₃)alkyl,(C₁–C₃)alkoxy, CN, OH, halo, CF₃, and NR⁸R⁸; R¹⁰ is selected from H and(C₁–C₃)alkyl; Z is selected from CH₂, O, S and NH, and when Z is NH, His optionally replaced with pyridyl, (C₁–C₃)alkyl optionally substitutedwith a substituent selected from hydroxy, (C₁–C₃)alkoxy and pyridyl, orphenyl optionally substituted with 1, 2, or 3 substituents eachindependently selected from (C₁–C₃)alkyl, (C₁–C₃)alkoxy, CN, halo, CF₃,and NR⁸R⁸; or a pharmaceutically acceptable salt or ester thereof,excluding the following compounds:5,6,7,8-tetrahydro-7-methyl-N-[4-phenylmethoxy)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine,monohydrochloride;5,6,7,8-tetrahydro-N-(4-methoxyphenyl)-7-methyl-[1]benzothieno[2,3-d]pyrimidin-4-amine,monohydrochloride;5,6,7,8-tetrahydro-7-methyl-N-[3-(trifluoromethyl)phenyl]-[1]benzothieno-[2,3-d]pyrimidin-4-amine;N-(3,4-dimethylphenyl)-5,6,7,8-tetrahydro-7-methyl[1]benzothieno-[2,3-d]pyrimidin-4-amine.
 3. A process for preparing acompound according to claim 1, wherein a compound of formula (II)

wherein R has the meaning indicated in claim 1, is reacted with acompound of formula (III)

wherein R¹ to R⁵ have the meaning indicated in claim
 1. 4. Apharmaceutical composition comprising a compound according to claim 1.5. A pharmaceutical composition comprising a compound of claim 1 incombination with at least one pharmaceutically acceptable,pharmaceutically safe carrier or excipient.
 6. A process for preparing apharmaceutical composition according to claim 5, comprising combining atleast one compound according to claim 1 with at least onepharmaceutically acceptable, pharmaceutically safe carrier or excipient.7. A method of treating lung or breast cancer in a mammal comprisingadministering to a mammal in need thereof an effective amount of acompound of formula (I).